Thermal shock protein-regulating conjugate and use thereof

Abstract

The present invention relates to a novel compound selected from a protein degrader or conjugate including a PI3K target moiety and an HSP90 target moiety linked through a linker, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The compound can treat cancer through a degradation pathway of a heat shock protein conjugate.

Description

Heat shock protein regulatory conjugates and uses thereof

[0001] The present invention provides formulations referencing heat shock protein modulatory conjugates and related applications. More specifically, the present invention relates to a target compound for treating cancer via the degradation pathway of a heat shock protein conjugate, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient for preventing, alleviating, or treating diseases caused by abnormal cell growth.

[0002] This invention was made possible with the support of the National New Drug Development Project of the National Drug Development Agency with funds from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare (2710069153, RS-2024-00462810).

[0003] Targeted delivery of cancer-specific cytotoxic agents has been most extensively pursued through conjugation of drugs to tumor-specific antibodies (ADCs). ADCs and recently developed ligand-drug conjugates are characterized by their reliance on differential expression of cell surface receptors on tumor cells compared to all normal cells. Another approach is to target altered states of the cancer cell proteome. For example, elevated stress levels in tumor cells are thought to induce the formation of large protein complexes composed of molecular chaperones and scaffolding proteins. Heat shock protein 90 (HSP90), a key component of "Epichaperon," is an intracellular chaperone protein that helps fold dozens of important client proteins in cells and stabilizes proteins against heat stress. It is upregulated in many types of cancer. Heat shock proteins, which are more overexpressed in tumor cells than in normal cells, have the functional property of binding tightly (slow off-rate) to HSP90 inhibitors. As a result, HSP90 inhibitors can persist in tumors for a long time, and tumors have a half-life that is more than 10 times longer than that in normal tissues. Therefore, HSP90 has been considered a major target for anticancer drug development for the past several decades. PEN-866 is an HSP90i-SN38 conjugate that can deliver a topoisomerase inhibitor tumor-selectively through a linker hydrolyzable by carboxylesterase (CES). PEN-866 has shown promise in preclinical models. Although PhII phase progressed, CES hydrolysis activity in tumor cells is highly variable, and thus, depending on tumor CES expression, may result in highly variable efficacy.

[0004] The phosphoinositide 3-kinase (PI3K) pathway plays a crucial role in cell growth, metabolism, and survival. Activation of PI3K signaling has been found in several tumor types due to mutations in several genes, including tyrosine kinase receptors and PI3K, or deletions of the tumor suppressor PTEN. PIK3CA, the gene encoding the catalytic subunit of PI3K, is frequently altered (mutated and amplified) in breast invasive carcinomas (34%), uterine cancer (53%), lung squamous cell carcinoma (44%), and colorectal cancer (25%) (TCGA / cbioportal). Therefore, the discovery of PI3K inhibitors has been an area of ​​intense drug development for over 20 years, with dozens of PI3K inhibitors with varying specificities entering the clinic. Among them, alpelisib, a selective PI3K inhibitor, was recently approved for PIK3CA-mutant, ER+, HER2- breast cancer (the first approval for a solid tumor indication; there are four PI3K inhibitors approved for lymphoma / leukemia). Other compounds tested in solid tumors, such as the pan-PI3K inhibitors BKM120 and CLR457, have been discontinued due to toxicity issues. Because the PI3K pathway plays a central role in many cell types, all PI3K inhibitors are associated with on-target and off-tissue toxicities when administered systemically. Toxicity associated with oral systemic PI3K inhibitor exposure includes hyperglycemia, rash, and gastrointestinal upset. Therefore, while cancer genetics and preclinical efficacy studies suggest that PI3K inhibitors can be highly effective targeted therapies, their use is limited by tolerability issues. Alpelisib is effective in treating PIK3CA-mutant breast cancer, but its benefit to patients may be limited due to side effects associated with high doses (≥450 mg).Therefore, more patients may benefit from the development of PI3K mutation-selective inhibitors or degraders with fewer drug side effects and superior efficacy. Therefore, the present invention aims to design and synthesize an HSP90i-PI3Ki conjugate by introducing a hydrolytically stable linker for the treatment of recurrent or metastatic breast cancer with PIK3CA mutations.

[0005] An object of the present invention is to provide a compound selected from a protein degrader or conjugate comprising a PI3K targeting moiety and an HSP90 targeting moiety linked via a linker, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0006] Another object of the present invention is to provide a pharmaceutical composition for treating or preventing cancer, comprising as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0007] Another object of the present invention is to provide a health functional food composition for improving or preventing cancer, which comprises as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0008] Another object of the present invention is to provide a method for treating a disease related to heat shock protein 90 (HSP90) or phosphoinositide 3-kinase (PI3K), comprising a step of administering a compound selected from the protein decomposition agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0009] Another object of the present invention is to provide a method for degrading HSP90 or PI3K target proteins, comprising a step of administering a compound selected from the protein degrading agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0010] In order to achieve the above object, the present invention provides a protein degrader or conjugate comprising a phosphoinositide 3-kinase (PI3K) target moiety and a heat shock protein 90 (HSP90) target moiety linked via a linker, represented by the following chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, a compound selected from:

[0011] [Chemical Formula 1]

[0012] XLY

[0013] In the above chemical formula 1, X is a PI3K targeting moiety, L is a linker, and Y is an HSP90 targeting moiety.

[0014] The present invention provides a pharmaceutical composition for treating or preventing cancer, comprising as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0015] The present invention provides a health functional food composition for improving or preventing cancer, comprising as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0016] The present invention provides a method for treating a disease related to heat shock protein 90 (HSP90) or phosphoinositide 3-kinase (PI3K), comprising a step of administering a compound selected from the protein decomposition agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0017] In addition, the present invention provides a method for degrading HSP90 or PI3K target proteins, comprising a step of administering a compound selected from the protein degrading agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0018] The present invention relates to a novel compound selected from a protein degrading agent or conjugate comprising a PI3K target moiety and an HSP90 target moiety linked via a linker, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which can treat cancer through a target protein degradation pathway by forming an HSP90i-PI3Ki conjugate through introduction of a hydrolytically stable linker, and can be utilized as a variety of treatment methods and therapeutic agents.

[0019] Hereinafter, the present invention will be described in more detail.

[0020] The present invention provides a protein degrader or conjugate comprising a phosphoinositide 3-kinase (PI3K) targeting moiety and a heat shock protein 90 (HSP90) targeting moiety linked via a linker, represented by the following chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, a compound selected from:

[0021] [Chemical Formula 1]

[0022] XLY

[0023] In the above chemical formula 1, X is a PI3K target moiety, L is a linker, Y is an HSP90 target moiety, and may specifically have a structure of chemical formulas 1-1 to 1-14, and the target ligand is not limited to a small molecule compound and may include a peptide, an antibody analog, a hexamer, an antibody, a carbohydrate, and a fat:

[0024] [Chemical Formula 1-1]

[0025]

[0026] [Chemical Formula 1-2]

[0027]

[0028] [Chemical Formula 1-3]

[0029]

[0030] [Chemical Formula 1-4]

[0031]

[0032] [Chemical Formula 1-5]

[0033]

[0034] [Chemical Formula 1-6]

[0035]

[0036] [Chemical Formula 1-7]

[0037]

[0038] [Chemical Formula 1-8]

[0039]

[0040] [Chemical Formula 1-9]

[0041]

[0042] [Chemical Formula 1-10]

[0043]

[0044] [Chemical Formula 1-11]

[0045]

[0046] [Chemical Formula 1-12]

[0047]

[0048] [Chemical Formula 1-13]

[0049]

[0050] [Chemical Formula 1-14]

[0051]

[0052]

[0053] In the above chemical formula 1, X may have any one of the structures of the following chemical formulas 2 to 7:

[0054] [Chemical Formula 2]

[0055]

[0056] [Chemical Formula 3]

[0057]

[0058] [Chemical Formula 4]

[0059]

[0060] [Chemical Formula 5]

[0061]

[0062] [Chemical Formula 6]

[0063]

[0064] [Chemical Formula 7]

[0065]

[0066] In the above chemical formula 2, is a single bond or a double bond, m1 and m2 may be the same or different and are 0 or 1, A1 to A5 may be the same or different and are any one of C, CH, CF, CH2, N and NH, and R 1 is any one of hydrogen, morpholino and amino substituted pyrimidyl, and R 2 is any one of halogen, unsubstituted or substituted aryl having 4 to 10 carbon atoms and substituted heteroaryl having 5 to 10 atoms containing at least one heteroatom selected from the group consisting of N, O and S, wherein the substituted aryl and substituted heteroaryl are substituted with at least one selected from the group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Boc, trifluoromethyl and halogen, and R 3 and R 4 may be the same or different, and are hydrogen or halogen, or R 3 and R 4 may be linked to each other to form a 4 to 6 membered heteroaryl containing one or more heteroatoms selected from N or S.

[0067] In the above chemical formula 3, R 5 and R 6 may be the same or different, and are hydrogen, (C1-C5)alkyl, or R 5 and R 6 can be linked to each other to form aryls of 4 to 6 atoms.

[0068] In the above chemical formula 4, R7 Inland R 10 may be the same or different, and may be hydrogen, halogen, or trifluoromethyl.

[0069] In the above chemical formula 5, R 11 Inland R 14 may be the same or different, and may be hydrogen, (C1-C5)alkyl, halogen or trifluoromethyl.

[0070] In the above chemical formula 6, R 15 Inland R 17 may be the same or different, and may be hydrogen, (C1-C5)alkyl, halogen, amino, or (C1-C5)alkylsulfonamino.

[0071] In the above chemical formula 7, R 18 may be selected from hydrogen or (C1-C5)alkyl.

[0072] Preferably, the above chemical formula 2 may be one of the following chemical formulas 2-1 to 2-10:

[0073] [Chemical Formula 2-1]

[0074]

[0075] [Chemical Formula 2-2]

[0076]

[0077] [Chemical Formula 2-3]

[0078]

[0079] [Chemical Formula 2-4]

[0080]

[0081] [Chemical Formula 2-5]

[0082]

[0083] [Chemical Formula 2-6]

[0084]

[0085] [Chemical Formula 2-7]

[0086]

[0087] [Chemical Formula 2-8]

[0088]

[0089] [Chemical Formula 2-9]

[0090]

[0091] [Chemical Formula 2-10]

[0092]

[0093] The above R 2 is any one selected from the group consisting of halogen, morpholino, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted indazolyl, and unsubstituted or substituted phenyl, wherein the substituted pyridinyl, pyrimidyl, benzoxazolyl, indazolyl, and substituted phenyl may be substituted with at least one selected from the group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Boc, trifluoromethyl, and halogen.

[0094] Preferably, the above chemical formula 3 may be the following chemical formula 3-1 or 3-2:

[0095] [Chemical Formula 3-1]

[0096]

[0097] [Chemical Formula 3-2]

[0098]

[0099] Preferably, in the above chemical formula 4, R 7 Inland R 10 may be the same or different, and are fluorine, chlorine or trifluoromethyl, and in the above formula 5, R 11 Inland R 14may be the same or different, and are (C1-C2)alkyl, fluorine or trifluoromethyl, and in the above formula 6, R 15 Inland R 17 may be the same or different, and are (C1-C2)alkyl, chlorine, amino, or (C1-C2)alkylsulfonamino, and R in the above chemical formula 7 18 may be, but is not limited to, (C1-C3)alkyl.

[0100] In the above chemical formula 1, Y may have any one of the structures of the following chemical formulas 8 to 12:

[0101] [Chemical Formula 8]

[0102]

[0103] [Chemical Formula 9]

[0104]

[0105] [Chemical Formula 10]

[0106]

[0107] [Chemical Formula 11]

[0108]

[0109] [Chemical Formula 12]

[0110]

[0111] In the above chemical formula 8, B1 to B5 may be the same or different and are C, CH, CH2 or N, and R 19 is hydrogen or amino, and R 20 is hydrogen or oxygen, and R 20 When this is oxygen is a double bond, and R 21 Inland R 24 may be the same or different, and is any one of hydrogen, halogen, hydroxy, benzyloxy, (C1-C5)alkyl or (C1-C5)alkoxy; R 21 and R 22 , R 22 and R23 , or R 23 and R 24 are linked to each other to form a 4 to 6-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O, and in the above formula 9, R 25 Inland R 28 may be the same or different, and are hydrogen, hydroxy or (C1-C5)alkyl, and in the above formula 10, R 29 Inland R 32 may be the same or different, and are hydrogen, halogen, amino, or (C1-C5)alkyl, and in the above formula 11, R 33 Inland R 35 may be the same or different, and are hydrogen, (C1-C5)alkyl, halogen or trifluoromethyl, and R 36 and R 37 may be the same or different, and are hydrogen or (C1-C5)alkyl, or R 36 and R 37 These are interconnected to form a six-ring ring, R 38 is hydrogen or (C1-C5)alkyl, m3 is 0 or 1, and in the above chemical formula 12, R 39 Inland R 42 may be the same or different, and may be selected from hydrogen, halogen, amino, (C1-C5)alkyl or (C1-C5)alkoxy.

[0112] Preferably, the above chemical formula 8 may be the following chemical formula 8-1 or 8-2:

[0113] [Chemical Formula 8-1]

[0114]

[0115] [Chemical Formula 8-2]

[0116]

[0117] The above R 21 Inland R 24may be the same or different, and are any one of hydrogen, halogen, hydroxy, benzyloxy, (C1-C3)alkyl or (C1-C3)alkoxy; R 21 and R 22 or R 22 and R 23 can be linked to each other to form a 5-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O.

[0118] Preferably, in the above chemical formula 9, R 25 Inland R 28 may be the same or different, and are hydrogen, hydroxy or (C1-C3) alkyl, and in the above formula 10, R 29 Inland R 32 may be the same or different, and are hydrogen, chlorine, amino, or (C1-C3) alkyl, and in the above formula 11, R 33 Inland R 35 may be the same or different, and are hydrogen, (C1-C3)alkyl, or trifluoromethyl, and the R 36 and R 37 may be the same or different, and are hydrogen or (C1-C3)alkyl; R 36 and R 37 These are interconnected to form a six-ring ring, R 38 is hydrogen or (C1-C3)alkyl, m3 is 0 or 1, and in the above chemical formula 12, R 39 Inland R 42 may be the same or different, and may be selected from hydrogen, fluorine, amino, (C1-C3)alkyl or (C1-C3)alkoxy, but are not limited thereto.

[0119] In the above chemical formula 1, L may have a structure of the following chemical formula 13:

[0120] [Chemical Formula 13]

[0121]

[0122] The above n is 1 to 30, and the above L' is each independently -CH2-, -CO-, -CH(CH3)-, -(CH)2-, -COO-, -OCO-, -NR 101 -, -CHOH-, -CONH-, -NHCO-, -O-, -SO2-, -PO(OH)-, -PO(OCH3)-, , , unsubstituted or substituted cycloalkylene having 3 to 10 carbon atoms, unsubstituted or substituted 4 to 20-membered heterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted arylene having 3 to 10 carbon atoms, unsubstituted or substituted 4 to 20-membered heteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted spirocycloalkylene having 5 to 10 carbon atoms, unsubstituted or substituted 5 to 13-membered spiroheterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted 5 to 13-membered spiroheteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, bicycloalkylene having 5 to 10 carbon atoms and N, Any one of 5 to 10-membered heterobicycloalkylenes containing at least one heteroatom selected from the group consisting of O and S, wherein R 101 Silver hydrogen, (C1-C5)alkyl and is one of, and n3 is one of 1 to 5, and R 102 and R 103may be the same or different, and are hydrogen or (C1-C5)alkyl, wherein n1 is one of 1 to 10, and the substituted cycloalkylene, heterocycloalkylene, arylene, heteroarylene, spirocycloalkylene, spiroheterocycloalkylene, spiroheteroarylene, bicycloalkylene and heterobicycloalkylene are hydroxy, carboxy, carbonyl, halogen, (C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Fmoc (fluorenylmethyloxycarbonyl), , at least one selected from the group consisting of morpholino(C1-C5)alkyl, and (C1-C5)alkylsulfonyl is substituted, and n2 may be one of 1 to 10.

[0123] Preferably, the n is 1 to 15, and the L is each independently -CH2-, -CO-, -CH(CH3)-, -(CH)2-, -COO-, -OCO-, -NR 101 -, -CHOH-, -CONH-, -NHCO-, -O-, -SO2-, -PO(OH)-, -PO(OCH3)-, , , , unsubstituted or substituted cycloalkylene having 3 to 6 carbon atoms, unsubstituted or substituted 4 to 20-membered heterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted arylene having 4 to 6 carbon atoms, unsubstituted or substituted 4 to 20-membered heteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted spirocycloalkylene having 5 to 10 carbon atoms, unsubstituted or substituted 5 to 13-membered spiroheterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted 5 to 13-membered spiroheteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, bicycloalkylene having 5 to 10 carbon atoms and N, O and Any one of 5 to 10-membered heterobicycloalkylenes containing at least one heteroatom selected from the group consisting of S, wherein R 101 is hydrogen, (C1-C3)alkyl, and wherein n3 is one of 1 to 5, and n1 is one of 1 to 5, and the substituted cycloalkylene, heterocycloalkylene, arylene, heteroarylene, spirocycloalkylene, spiroheterocycloalkylene, spiroheteroarylene, bicycloalkylene and heterobicycloalkylene are selected from the group consisting of hydroxy, carboxy, carbonyl, halogen, (C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Fmoc, , at least one selected from the group consisting of morpholino(C1-C2)alkyl, and (C1-C2)alkylsulfonyl is substituted, and n2 may be one of 1 to 5.

[0124] Specifically, the cycloalkylene, heterocycloalkylene, arylene, heteroarylene, spirocycloalkylene, spiroheterocycloalkylene, spiroheteroarylene, bicycloalkylene and heterobicycloalkylene are piperidine, pyridine, piperazine, pyrazine, phenyl, benzyl, pyrazole, triazole, hydropyrrolopyrrole and azetidine. It may be selected from morpholine, 5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine, 5,6-dihydroimidazo[1,2-α]pyrazine, 3,9-diazaspiro[5.5]undecane, 1-oxa-8-azaspiro[4.5]decane, 1-oxa-4,9-diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, diazepane, tetraoctadiazacyclooctadecane, bicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, or 3,8-diazabicyclo[3.2.1]octane, but is not limited thereto.

[0125] More preferably, the compound may be selected from the following group of compounds:

[0126] (1) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (2) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethan-1-one; (3) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (4) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (5) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (6) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butan-1-one; (7) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(8) 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (9) 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one; (10) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (11) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (12) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (13) (4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (14) (4-(2-(2-aminobenzo[d]oxazol-6-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(15) (4-(2-(1H-indazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (16) (5-((4-(4-(2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (17) (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (18) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)phenyl)methanone; (19) (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (20) (5-((4-(2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (21) (5-((5-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(22) (5-((4-((6-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-3-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (23) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone; (24) (5-((4-(4-(2-(1H-indazol-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (25) (S)-(5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (26) ((S)-3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)((S)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)pyrrolidin-3-yl)methanone; (27) (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone; (28) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(29) (5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (30) (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (31) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (32) 2-amino-4-(5-(2-(4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperazin-1-yl)ethoxy)-2,4-dichlorophenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide; (33) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)methanone; (34) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (35) (4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(36) (5-((4-((1r,4r)-4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (37) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)sulfonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (38) 2-((1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperidin-4-yl)amino)-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; (39) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (40) (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (41) (5-(((R)-4-(((1r,4R)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(42) 2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)propan-1-one; (43) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-fluorobenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (44) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)propan-1-one; (45) (S)-(5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (46) (5-((9-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (47) (5-((4-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (48) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)propan-1-one;(49) (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (50) (S)-(5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (51) (5-((4-(2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)-2-hydroxyethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (52) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (53) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (54) (R)-2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one;(55) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (56) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (57) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (58) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (59) 1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (60) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(61) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (62) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (63) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (64) (S)-(5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholine-4-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (65) 1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (66) (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone;(67) (S)-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (68) (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (69) (5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (70) 1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (71) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (72) (5-((1-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(73) (S)-(5-((4-((1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclopropyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (74) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (75) (S)-(5-((4-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (76) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (77) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (78) (S)-2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one;(79) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-((R)-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)propan-1-one; (80) (5-((4-((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (81) (5-((4-((1-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (82) (S)-(5-((4-((2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholino)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (83) (S)-1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholino)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (84) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone;(85) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (86) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (87) (5-((4-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (88) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (89) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (90) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)ethan-1-one;(91) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)ethan-1-one; (92) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)amino)piperidin-1-yl)ethan-1-one; (93) (5-(((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)(2-(2-methoxyethoxy)ethyl)amino)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (94) (5-(2-(1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)-5,8,11,14-tetraoxa-2-azapentadecyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (95) N-(15-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide; (96) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)acetamide;(97) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-N-(2,5,8,11-tetraoxatrican-13-yl)acetamide; (98) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide; (99) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)cyclohexyl)methanone; (100) (5-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)propoxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (101) (5-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)propoxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (102) (4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (103) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one;(104) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)ethan-1-one; (105) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (106) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)cyclohexyl)methanone; (107) (4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (108) 1-(4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (109) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(110) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (111) (2-(2-Aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (112) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (113) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)azetidin-1-yl)ethan-1-one; (114) (5-((4-(4-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (115) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (116) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide;(117) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (118) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (119) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(3-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxamide; (120) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(3-(4-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxamide; (121) (2R,4S)-4-(2-(4-(2-(5-(2-amino-6-(ethylcarbamoyl)thieno[2,3-d]pyrimidin-4-yl)-2,4-dichlorophenoxy)ethyl)piperazin-1-yl)-2-oxoethoxy)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2-dicarboxamide; (122) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide;(123) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (124) (S)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (125) (S)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (126) (S)-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (127) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (128) (4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (129) (4-(2'-amino-5-fluoro-6-morpholino-[4,5'-bipyrimidin]-2-yl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (130) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone;(131) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (132) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (133) (S)-(5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (134) (5-((4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-3-fluorobenzoyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (135) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (136) (5-((4-((1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (137) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (138) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone;(139) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (140) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)morpholin-2-yl)((S)-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (141) (4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (142) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (143) (5-((4-(8-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-8-azaspiro[4.5]decan-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (144) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (145) (7-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone;(146) (S)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (147) 1-(4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (148) (4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (149) (S)-2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (150) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (151) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (152) (R)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(153) (R)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (154) (R)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (155) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (156) (S)-2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (157) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (158) (4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (159) (4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(160) 1-(4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (161) 1-(4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (162) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (163) 2-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (164) 2-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (165) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (166) 2-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one;(167) 2-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (168) (5-((4-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)azetidin-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (169) (5-((2-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (170) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (171) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (172) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (173) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone;(174) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (175) 1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (176) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (177) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methanone; (178) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (179) (6-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (180) 6-(2-aminopyrimidin-5-yl)-N-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide;(181) (6-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (182) (6-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methanone; (183) (6-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (184) (6-(2-Aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (185) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (186) (2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (187) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (188) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one;(189) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (190) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethan-1-one; (191) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)ethan-1-one; (192) (S)-2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (193) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (194) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (195) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone;(196) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (197) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (198) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (199) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (200) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (201) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (202) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone;(203) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (204) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (205) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (206) (4-((5-(2-aminopyrimidin-5-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (207) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (208) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (209) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one;(210) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (211) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (212) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (213) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (214) (4-((6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (215) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (216) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone;(217) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (218) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (219) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (220) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (221) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone; (222) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(4-hydroxy-7-isopropylbenzo[d]isoxazole-5-carbonyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (223) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone;(224) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (225) (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (226) 1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (227) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)-[1,4'-bipiperidin]-1'-yl)methanone; (228) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)azetidin-1-yl)methanone; (229) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (230) 1-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one;(231) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (232) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (233) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(5-chloro-2,4-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (234) (5-((4-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (235) 1-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (236) (5-((4-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(237) (5-((4-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (238) 1-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (239) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (240) (5-((4-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (241) (5-((4-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (242) 1-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one;(243) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methanone; (244) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)amino)piperidin-1-yl)methanone; (245) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (246) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (247) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone; (248) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (249) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone;(250) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (251) (5-((7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (252) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)-3-fluorophenyl)methanone; (253) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)ethan-1-one; (254) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (255) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (256) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one;(257) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (258) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(4-hydroxy-5-isopropylbenzo[d]isoxazole-7-carbonyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (259) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (260) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (261) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (262) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (263) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(264) 1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (265) N-(2-(2-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide; (266) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (267) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (268) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)ethan-1-one; (269) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)ethan-1-one;(270) (R)-2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (271) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(methylsulfonyl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (272) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylpiperidine-4-carboxamide; (273) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)methanone; (274) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-(2-(2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperidine-4-carboxamide; (275) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methanone;(276) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methanone; (277) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one; (278) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide; (279) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)phenyl)methanone; (280) (5-((4-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)phenyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (281) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2,5,8,11-tetraoxatridecan-13-yl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone;(282) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2-(2-methoxyethoxy)ethyl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (283) Diethyl ((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phosphonate; (284) Diethyl ((4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)carbamoyl)phenyl)methyl)phosphonate; (285) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methanone; (286) (5-((4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (287) (5-((4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(288) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (289) (1'-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-[1,4'-bipiperidin]-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (290) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1'-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-[1,4'-bipiperidin]-4-yl)methanone; (291) (5-((4-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (292) (5-((4-(1-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperidin-4-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (293) (5-((9-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(294) (5-((2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (295) (5-((4-(1-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)azetidin-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (296) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1,4'-bipiperidin]-1'-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (297) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (298) N-(3-(2-chloro-5-fluorophenyl)-6-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (299) N-(3-(2-chloro-5-fluorophenyl)-6-(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (300) N-(4-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)phenyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide;(301) N-(3-(2-chloro-5-fluorophenyl)-6-(4-((2-(2-(2-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamoyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (302) N-(3-(2-chloro-5-fluorophenyl)-6-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (303) (5-((4-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)azetidin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (304) (5-((4-(4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (305) Methyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinate; (306) Ethyl hydrogen ((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phosphonate;(307) 2-(4-amino-1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (308) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (309) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinic acid; (310) Methyl (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinate; (311) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (312) (1-((2-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone;(313) (1-((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (314) (1-((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (315) (1-((2-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (316) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)azetidin-3-yl)methanone; (317) (1-((2-(6-amino-5-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (318) (1-((2-(6-amino-5-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (319) (S)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)methanone;(320) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(morpholinomethyl)piperazin-1-yl)methanone; (321) 2-(4-amino-1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (322) (1-((2-(5-amino-6-methoxypyrazin-2-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (323) (1-((2-(5-amino-6-methoxypyrazin-2-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (324) (5-((4-(4-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (325) (5-((4-((1-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(326) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (327) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (328) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (329) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (330) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)cyclohexyl)methanone; (331) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)cyclohexyl)methanone;(332) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidine-1-carbonyl)cyclohexyl)methanone; (333) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-carbonyl)cyclohexyl)methanone; (334) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)methanone; (335) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)methanone; (336) (6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (337) (1-((6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone;(338) 2-(4-amino-1-(6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-carbonyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (339) (2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (340) 2-(4-amino-1-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (341) Methyl (5-(6-(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrimidin-2-yl)carbamate; (342) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1S,4r)-4-((S)-4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)cyclohexyl)methanone; (343) Methyl(5-(2-((4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-8-morpholinoimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl)carbamate;(344) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)methanone; (345) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(5-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methoxy)pyrazin-2-yl)methanone; (346) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)methanone; (347) (1-((2-(6-amino-5-methylpyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (348) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pyrrolidin-3-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (349) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)((1r,4r)-4-(((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pyrazin-2-yl)oxy)methyl)cyclohexyl)methanone; (350) (1-((2-(6-amino-2-methylpyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone;(351) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1s,4s)-4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (352) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methanone; (353) (5-((4-(4-(((1r,4r)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (354) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)piperidin-1-yl)methanone; (355) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazin-1-yl)methanone; (356) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(5-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)methanone;(357) (4-amino-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone; (358) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)methanone; (359) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)phenyl)methanone; (360) (5-((4-((4'-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (361) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazin-1-yl)methanone; (362) (1-((2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (363) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)methanone;(364) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)piperidin-1-yl)methanone; (365) (5-((4-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclobutane-1-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (366) (1r,4r)-N-(6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-2-yl)-4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexane-1-carboxamide; (367) (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-5-yl)urea; (368) 1-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidin-1-yl)pyrimidin-5-yl)urea; (369) (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-((4-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)pyrimidin-5-yl)urea;(370) N-(6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)acetamide; (371) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone; (372) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-methylpiperidin-4-yl)(1'-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-[4,4'-bipiperidin]-1-yl)methanone; (373) (R)-N-(2-chloro-5-(4-((1-(3-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-oxopentyl)oxy)phenyl)ethyl)amino)quinazolin-6-yl)pyridin-3-yl)methanesulfonamide; (374) (1r,4r)-4-((1-oxo-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-1,2-dihydroisoquinolin-8-yl)amino)cyclohexyl 4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate; (375) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((6-(2,4-dihydroxy-5-isopropylbenzoyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)methyl)piperidin-1-yl)methanone;(376) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((6-(2,4-dihydroxy-5-isopropylbenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl)piperidin-1-yl)methanone; (377) (2-(2-Aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)phenyl)methanone; (378) (5-((4-((1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (379) (5-((4-((4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (380) (5-((4-((1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (381) (5-(4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (382) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide;(383) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (384) (2R,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (385) (2R,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (386) (R)-2-amino-6-(2-(1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one; (387) (R)-2-amino-6-(2-(1-((1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one; (388) (S)-6-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide;(389) (S)-6-(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide; (390) (S)-6-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide; (391) (1r,4r)-4-((1-oxo-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-1,2-dihydroisoquinolin-8-yl)amino)cyclohexyl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (392) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentane-1,5-dione; (393) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-fluoropiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (394) (1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone;(395) (6-(2-Aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (396) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)((1r,4r)-4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)cyclohexyl)methanone; (397) (E)-1-(4-(4-(2-Aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)but-2-ene-1,4-dione; (398) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (399) (5-((4-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (400) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(8-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone; (401) (5-((3-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone;(402) (1r,4r)-4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)cyclohexyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (403) 1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (404) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (405) (1r,4r)-4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carbonyl)cyclohexyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (406) 1-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carbonyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (407) (1r,4R)-4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)cyclohexyl(3-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propyl)carbamate;(408) (E)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)but-2-ene-1,4-dione; (409) 1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butane-1,4-dione; (410) (5-((4-(((1r,4r)-4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)cyclohexyl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (411) 2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (412) 4-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (413) 6-(2-Aminobenzo[d]oxazol-5-yl)-N-(3-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide; (414) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3,3-difluoropiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone;(415) (4-(2-((2-amino-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-6-yl)amino)ethyl)piperazin-1-yl)(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)methanone; (416) (4-(2-((2-amino-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-6-yl)amino)ethyl)piperazin-1-yl)(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)methanone; (417) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)((1r,3r)-3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)cyclobutyl)methanone; (418) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)azetidin-1-yl)methanone; (419) (1r,4r)-4-((2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (420) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)piperazin-2-one; (421) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)ethyl)piperazin-2-one;(422) 4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (423) 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)pyridin-2(1H)-one; (424) 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperidin-2-one; and (425) 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)pyridin-2(1H)-one.;

[0127] The present invention provides a pharmaceutical composition for treating or preventing cancer, comprising as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0128] The above cancer disease may be selected from the group consisting of breast cancer, lung cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophagus cancer, thyroid cancer, kidney cancer, and rectal cancer, but is not limited thereto.

[0129] The above cancer disease may be a cancer disease related to heat shock protein 90 (HSP90) or phosphoinositide 3-kinase (PI3K).

[0130] The above pharmaceutical composition can inhibit the activity of HSP90 or PI3K.

[0131] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, glidants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0132] Specifically, carriers, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspending agents can be propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Base materials for suppositories include witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin.

[0133] According to one embodiment of the present invention, the pharmaceutical composition can be administered to a subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes.

[0134] The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and degree of the disease, the drug form, the route and period of administration, and may be appropriately selected by a person skilled in the art, and the daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. Administration may be once a day or divided into several times, and the scope of the present invention is not limited thereby.

[0135] The present invention provides a health functional food composition for improving or preventing cancer, comprising as an active ingredient a compound selected from the protein decomposing agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0136] The above cancer disease may be selected from the group consisting of breast cancer, lung cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophagus cancer, thyroid cancer, kidney cancer, and rectal cancer, but is not limited thereto.

[0137] The above health functional food may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0138] In addition, it may contain fruit pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. Furthermore, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol, and vitamin complex.

[0139] In addition, the above health functional food may additionally contain food additives, and its suitability as a “food additive” is determined by the specifications and standards for the relevant item in accordance with the general provisions and general testing methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise provided.

[0140] Examples of items listed in the above "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kohlrabi pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0141] At this time, the content of the effective ingredient added to the food during the process of manufacturing the health functional food can be appropriately increased or decreased as needed, and preferably, it can be added so that it is included in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0142] The present invention provides a method for treating a disease related to heat shock protein 90 (HSP90) or phosphoinositide 3-kinase (PI3K), comprising a step of administering a compound selected from the protein decomposition agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0143] The present invention provides a method for degrading HSP90 or PI3K target proteins, comprising administering a compound selected from the protein degrading agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0144] In addition, the present invention provides a reagent composition for decomposing HSP90 or PI3K target proteins, comprising as an active ingredient a compound selected from the protein decomposition agent or conjugate thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0145] Hereinafter, to aid understanding of the present invention, examples and other embodiments will be described in detail. However, the following examples and other embodiments merely illustrate the content of the present invention and are not intended to limit the scope of the present invention. The examples and other embodiments of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0146] The following representative synthetic examples, working examples, and experimental examples are intended to illustrate the present disclosure and are not intended to limit the scope of the present invention. The examples below were prepared using the general synthetic method AG, modified synthetic methods, or reported examples.

[0147] [Synthesis Example 1] General Synthesis Method

[0148] (1) Synthesis method A

[0149] 1) Reductive amination (aldehyde)

[0150] An amine compound (1 eq) and an aldehyde compound (1.1 eq) were dissolved in CH2Cl2 (0.2 M) (or DMF, ClCH2CH2Cl). If the starting material contained a hydrochloride, DIPEA (2 eq) was added and stirred for 5 minutes. NaBH(OAc)3 (2.2 eq) was added and stirred for 2 to 24 hours at room temperature (or heated to 60°C if necessary). The reaction mixture was mixed with a saturated aqueous sodium bicarbonate solution and extracted using DCM or IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding product.

[0151] 2) Reductive amination (ketone)

[0152] An amine compound (1 eq) and a ketone compound (1.1 eq) were dissolved in CH2Cl2 (0.2 M) (or DMF, ClCH2CH2Cl). If the starting material contained a hydrochloride, DIPEA (2 eq) was added and stirred for 5 minutes. Acetic acid (3.0 eq) and NaBH(OAc)3 (2.2 eq) were added and stirred at room temperature for 2 to 24 hours. The reaction mixture was mixed with a saturated aqueous sodium bicarbonate solution and extracted using DCM or IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding product.

[0153] (2) Synthesis method B: Amide bond reaction

[0154] Amine compound (1 eq) and carboxylic acid compound (1 eq) were dissolved in DMF (0.2 M)(CH2Cl2). iPr2EtN (3 eq), EDCI HCl (2 eq), and HOAt (or HOBt) (2 eq) were added to the reaction mixture and stirred at room temperature (heated to 60°C if necessary) for 2 to 24 hours. The reaction mixture was mixed with a saturated aqueous sodium bicarbonate solution and extracted using IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding amide product.

[0155] (3) Synthesis method C: Hydrolysis reaction

[0156] 1) Deprotection of Boc-protected amine

[0157] The Boc-protected amine compound (1 eq) was dissolved in a 4.0 M hydrochloric acid solution in 1,4-dioxane (5 eq) and stirred at room temperature (warmed as needed) for 4 to 24 h. The reaction mixture was concentrated under reduced pressure to obtain the corresponding amine hydrochloride product.

[0158] 2) Ester hydrolysis

[0159] - Hydrolysis under acidic conditions: The ester compound (1 equivalent) was dissolved in a 1,4-dioxane solution, and then 35% aqueous hydrochloric acid solution (50 equivalents) was added dropwise and stirred at 80°C for 8 to 24 hours. The reaction mixture was concentrated under reduced pressure to obtain the corresponding carboxylic acid product.

[0160] - Hydrolysis under basic conditions: The ester compound (1 equivalent) was dissolved in THF / H2O (10:1), and 1.5 equivalents of LiOH (or NaOH, K2CO3) were added dropwise, and the mixture was stirred at room temperature for 8 to 24 hours. The reaction mixture was concentrated under reduced pressure to obtain the corresponding carboxylic acid product.

[0161] (4) Synthesis method D: Suzuki-Miyaura coupling

[0162] An organoboron compound (1.1 eq) and K2CO3 (or Cs2CO3, KOH, Na2CO3, KF, etc.) (2 eq) were added to the reaction mixture of aryl bromide or aryl iodide (1 eq) dissolved in a 1,4-dioxane / water 5:1 (0.2 M) solvent, and the gas inside the solution was removed using a nitrogen balloon and an ultrasonic cleaner for 15 min. 0.05 eq Pd(PPh3)4 (or PdCl2PPh3, PdCl2DPPFCH2Cl2, X-phos, etc.) was added to the reaction mixture, and the mixture was stirred at 100°C for 4 to 24 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding product.

[0163] (5) Synthesis method E: Alkylation reaction

[0164] Amine or hydroxy compound (1 eq) and 1.2 eq of tosylated compound (or mesylated compound, bromoalkyl) were dissolved in DCM or THF, 1,4-dioxane, DMF, DMSO (0.2 M). NaH or, t BuOK, K2CO3 (1 to 2 equivalents) were added and stirred at room temperature (60°C, 100°C as needed) for 2 to 24 hours. The reaction mixture was mixed with water and extracted with DCM or IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding product.

[0165] (6) Synthetic method F: Substitution reaction

[0166] Fluorinated aryl or chlorinated aryl (1 eq) was dissolved in DCM or DMF, 1,4-dioxane (0.6 M), and cooled to 0°C. DIPEA (2 eq) and an amine compound (1 eq) were added to the reaction mixture, and the mixture was stirred at 0°C (or at room temperature or 100°C, as needed) for 1 to 24 hours. The reaction mixture was mixed with water and extracted using DCM or IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding product.

[0167] (7) Synthetic method G: Debenzylation reaction

[0168] 1) Benzyl ether compound (1 eq.), K2CO3 (2 eq.), and 10% Pd / C (20 wt.%) were dissolved in a methanol / water 10:1 (0.2 M) solvent, reduced to vacuum, and air was removed using a H2 balloon (repeated three times), then stirred for 4 to 24 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding phenol product.

[0169] 2) Benzyl ether compound (1 equivalent) was dissolved in 20 equivalents of triflic acid (or CF3CO2H (100 equivalents)) and stirred at room temperature for 1 to 3 hours. The reaction mixture was concentrated under reduced pressure, mixed with a saturated aqueous sodium bicarbonate solution, and extracted using an IPA / CHCl3 (1:3) solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding phenol product.

[0170] 3) Benzyl ether compound (1 eq) and pentamethyl benzene (3 eq) were dissolved in DCM (0.2 M) and cooled to -78°C. 1.0 M BCl3DCM solution (2 eq) was slowly added dropwise, and the mixture was stirred for 1 to 24 hours. A 1:10 methanol / CHCl3 solvent was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding phenol product.

[0171] 4) Benzyl ether compound (1 eq) and Pd(OH)2 (0.1 eq) were dissolved in methanol / THF 1:10 (0.2 M), vacuum-reduced, air was removed using a H2 balloon (repeated three times), and the mixture was stirred at room temperature for 4 to 24 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding phenol product.

[0172] 5) Benzyl ether compound (1 eq.), sodium bicarbonate (3 eq.), and Pd(OH)2 (0.1 eq.) were dissolved in water (0.2 M), vacuum-reduced, air was removed using a H2 balloon (repeated three times), and the mixture was stirred at room temperature for 4 to 24 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding phenol product.

[0173] (8) Synthetic method H: Deprotection of Fmoc-protected amine

[0174] The Fmoc-protected amine compound (1 eq) was dissolved in DMF (0.05 M), diethylamine (20 eq) was added, and the mixture was stirred at room temperature for 1 to 3 h. The reaction mixture was concentrated under reduced pressure. The mixture was purified by normal or reverse phase chromatography to obtain the corresponding amine product.

[0175] [Synthesis Example 2] Specific Synthesis of PI3K Inhibitor

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] (1) Representative synthesis example 1

[0196] The above P-3 synthetic route is specified below, and the synthesis of P-13 and P-19 was carried out using the same or modified synthetic route as the P-3 synthetic route.

[0197]

[0198] 1) Synthesis of intermediate 1 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 497 (M+H + )

[0199] 2) P-3 (5-(4-morpholino-7-(piperidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 397 (M+H + )

[0200] (2) Representative synthesis example 2

[0201] The above P-4 synthetic route is specified below.

[0202]

[0203] 1) Synthesis of intermediate 2 (4-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)morpholine): Synthesized using the above synthetic method C. ESI-MS m / z 255 (M+H + )

[0204] 2) Synthesis of intermediate 3 (tert-butyl 2-(2-chloro-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 369 (M+H + )

[0205] 3) Synthesis of intermediate 4 (tert-butyl 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetate): Synthesized using the above synthetic method D. ESI-MS m / z 495 (M+H + )

[0206] 4) P-4 (2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 439 (M+H + )

[0207] (3) Representative synthesis example 3

[0208] The above P-5 synthetic route is specified below. In addition, the synthesis of P-18, P-20, P-21, P-23, P-24, P-50, and P-93 was carried out using synthetic routes identical to or modified from the P-5 synthetic route.

[0209]

[0210] 1) Synthesis of intermediate 1 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydro[3,4-d]pyrimidine-7-carbonyl)piperidine-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 525 (M+H + )

[0211] 2) Synthesis of P-5 ((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(piperidin-4-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 425 (M+H + )

[0212] (4) Representative synthesis example 4

[0213] The above P-6 synthetic route is specified below. In addition, the synthesis of P-7 and P-8 was carried out using the same or modified synthetic route as the P-6 synthetic route.

[0214]

[0215] 1) Synthesis of intermediate 2 (tert-butyl 4-(2-chloro-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidine-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 466 (M+H + )

[0216] 2) Synthesis of intermediate 3 (tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidine-1-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 592 (M+H + )

[0217] 3) P-6 ((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(piperidin-4-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 492 (M+H + )

[0218] (5) Representative synthesis example 5

[0219] The synthetic route of P-9 is specified below. In addition, the synthesis of P-10 and P-12 was carried out using the same or modified synthetic route as the P-9 synthetic route.

[0220]

[0221] 1) Synthesis of intermediate 2 (tert-butyl 2-(2-aminobenzo[d]oxazol-6-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 453 (M+H + )

[0222] 2) Synthesis of P-9 (6-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)benzo[d]oxazol-2-amine): Synthesized using the above synthetic method C. ESI-MS m / z 353 (M+H + )

[0223] (6) Representative synthesis example 6

[0224] The synthetic route of P-14 is given below.

[0225]

[0226] 1) Synthesis of intermediate 2 (tert-butyl 4-(2-aminopyridin-5-yl)-2-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 363 (M+H + )

[0227] 2) Synthesis of intermediate 3 (tert-butyl 4-(2-aminopyrimidin-5-yl)-2-morpholino-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 414 (M+H + )

[0228] (7) Representative synthesis example 7

[0229] The above P-15 synthetic route is specified below. In addition, the synthesis of P-16 and P-17 was carried out using the same or modified synthetic route as the P-15 synthetic route.

[0230]

[0231] 1) Synthesis of intermediate 1 (tert-butyl 4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)sulfonyl)piperidine-1-carboxylate): To the above P-5 (300 mg, 0.71 mmol) was added DCM (20 mL), and then tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (200 mg, 0.71 mmol) was slowly added. At 0°C, Et3N (0.3 mL, 2.13 mmol) was slowly added. The mixture was stirred at room temperature for 24 hours. After completion of the reaction, extraction was performed using DCM and H2O. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by MPLC (MeOH / DCM) to obtain intermediate 1. ESI-MS m / z 672 (M+H + )

[0232] 2) P-15 ((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(1-(piperidin-4-ylsulfonyl)piperidin-4-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 572 (M+H + )

[0233] (8) Representative synthesis example 8

[0234] The synthetic route of P-22 (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazine-2-carboxylic acid) is given below.

[0235]

[0236] : It was synthesized using the above synthetic method F. ESI-MSm / z436 (M+H + )

[0237] (9) Representative synthesis example 9

[0238] The synthetic route for P-25 is specified below. In addition, the synthesis of P-102 and P-103 was carried out using the same or modified synthetic route.

[0239]

[0240] 1) Synthesis of intermediate 2 (tert-butyl 2-chloro-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 341 (M+H + )

[0241] 2) Synthesis of intermediate 3 (tert-butyl 2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 400 (M+H + )

[0242] 3) P-83 (5-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 300 (M+H + )

[0243] 4) Synthesis of intermediate 5 (methyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)cyclohexene-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 468 (M+H + )

[0244] 5) P-25 (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-6-carbonyl)cyclohexene-1-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 454 (M+H + )

[0245] (10) Representative synthesis example 10

[0246] The synthetic route of P-26 is specified below. In addition, the synthesis of P-30, P-45, P-46, and P-86 was carried out using the same or modified synthetic route.

[0247]

[0248] 1) Synthesis of intermediate 2 (4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine): Synthesized using the above synthetic method F. ESI-MS m / z 256 (M+H + )

[0249] 2) Synthesis of P-44 (2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde): The solution of intermediate 2 (10 g, 39.1 mmol) dissolved in anhydrous THF (78.2 mL) was cooled to -78°C, n-BuLi (48.9 mL, 1.6 M in HEX, 78.2 mmol) was added dropwise, and the mixture was stirred at -78°C for 2 hours. DMF (6.06 mL, 78.2 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at -78°C for 3.5 hours. After that, saturated NH4Cl aqueous solution was added at room temperature to complete the reaction. The reaction mixture was washed with H2O, filtered under reduced pressure, and dried under vacuum at 45°C to obtain P-44. ESI-MS m / z 284 (M+H + )

[0250] 3) Synthesis of intermediate 3 (tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 454 (M+H + )

[0251] 4) Synthesis of intermediate 4 (tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate): Synthesized using the above synthetic method D ESI-MS m / z 513 (M+H + )

[0252] 5) P-26 (5-(4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 413 (M+H + )

[0253] (11) Representative synthesis example 11

[0254] The synthetic route for P-27 is specified below. In addition, the synthesis of P-105 and P-106 was carried out using the same or modified synthetic route.

[0255]

[0256] 1) Synthesis of intermediate 2 (ethyl 2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 311 (M+H + )

[0257] 2) Synthesis of intermediate 3 (ethyl 2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 370 (M+H + )

[0258] 3) Synthesis of P-27 (2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid): Synthesized using the above synthetic method C. ESI-MS m / z 342 (M+H + )

[0259] (12) Representative synthesis example 12

[0260] The synthetic route of P-28 is given below.

[0261]

[0262] 1) Synthesis of intermediate 1 (tert-butyl 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 527 (M+H + )

[0263] 2) P-28 (2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)acetic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 471 (M+H + )

[0264] (13) Representative synthesis example 13

[0265] The synthetic route of the above P-29 is specified below. In addition, the synthesis of the above P-31, P-32, P-36, P-87, P-94, P-95, P-96, P-97, P-98, P-99, P-100, and P-101 was carried out using the same or modified synthetic route as the P-29 synthetic route.

[0266]

[0267] 1) Synthesis of intermediate 1 (tert-butyl 1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 453 (M+H + )

[0268] 2) Synthesis of intermediate 2 (tert-butyl 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 512 (M+H + )

[0269] 3) P-29 (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 456 (M+H + )

[0270] (14) Representative synthesis example 14

[0271] The above P-33 synthetic route is specified below. In addition, the above P-37 synthesis was carried out using a synthetic route identical to or modified from the P-33 synthetic route.

[0272]

[0273] 1) Synthesis of intermediate 2 (tert-butyl 4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidine-1-carboxylate): A solution of intermediate 1 (1.5 g, 5.9 mmol) dissolved in anhydrous THF (50 mL) was cooled to -78°C, n-BuLi (7.3 mL, 1.6 M in HEX, 12 mmol) was added dropwise, and the mixture was stirred at -78°C for 2 hours. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) dissolved in anhydrous THF (9 mL) was added dropwise to the reaction mixture, and the mixture was stirred at -78°C for 3.5 hours. After that, a saturated NH4Cl aqueous solution was added at room temperature to complete the reaction. The reaction mixture was extracted using THF and H2O, and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by MPLC (HEX / THF) to obtain intermediate 2. ESI-MSm / z455 (M+H + )

[0274] 2) Synthesis of intermediate 3 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidine-1-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 514 (M+H + )

[0275] 3) P-33 (4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-ol) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 414 (M+H + )

[0276] (15) Representative synthesis example 15

[0277] The above P-34 synthetic route is specified below. In addition, the above P-35 synthesis was carried out using a synthetic route identical to or modified from the P-34 synthetic route.

[0278]

[0279] 1) Synthesis of intermediate 1 (tert-butyl 3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 652 (M+H + )

[0280] 2) P-34 (5-(6-((4-(1-Oxa-8-azaspiro[4.5]decan-3-yl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 552 (M+H + )

[0281] (16) Representative synthesis example 16

[0282] The above P-38 synthetic route is specified below.

[0283]

[0284] 1) Synthesis of intermediate 1 (tert-butyl (2-(2-(3-(4-((2-(2-aminopyrimidin-5-yl))-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)carbamate): Synthesized using the above synthetic method B. ESI-MS m / z 672 (M+H + )

[0285] 2) P-38 (3-(2-(2-aminoethoxy)ethoxy)-1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propan-1-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 572 (M+H + )

[0286] (17) Representative synthesis example 17

[0287] The synthetic route of P-39 is given below.

[0288]

[0289] 1) Synthesis of intermediate 2 (methyl 6-(2-aminopyrimidin-5-yl)imidazole[1,2-a]pyridine-3-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 270 (M+H + )

[0290] 2) P-39 (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid) synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 256 (M+H + )

[0291] (18) Representative synthesis example 18

[0292] The synthetic route of P-43 is given below.

[0293]

[0294] 1) Synthesis of intermediate 2 (ethyl 2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 311 (M+H + )

[0295] 2) Synthesis of intermediate 3 ((2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol): The intermediate 2 (1.1 g, 3.54 mmol) was dissolved in THF (35 mL) and cooled. LAH (156 mg, 3.89 mmol) was slowly added and stirred for 30 minutes. After completion of the reaction, it was cooled and quenched by slowly adding 5 mL of saturated NH4Cl aqueous solution, 5 mL H2O, and 15 mL EA. The resulting suspension was filtered through celite and washed with EA. The aqueous layer was saturated with NaCl and extracted with EA. The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 269 (M+H + )

[0296] 3) Synthesis of P-42 (2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbaldehyde): The intermediate 3 (951 mg, 3.54 mmol) was dissolved in DCM (117 mL), MnO2 (1.54 g, 17.7 mmol) was added, and the mixture was stirred for 5 hours. After completion of the reaction, the mixture was filtered through celite and washed with DCM. The obtained filtrate was concentrated under reduced pressure, and then purified by MPLC (EA / Hex) to obtain P-42. ESI-MS m / z 267 (M+H + )

[0297] 4) Synthesis of intermediate 4 (tert-butyl 1-((2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 436 (M+H+ )

[0298] 5) P-43 (1-((2-chloro-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 380 (M+H + )

[0299] (19) Representative synthesis example 19

[0300] The synthetic route of P-47 is specified below. In addition, the synthesis of P-48 and P-49 was carried out using the same or modified synthetic route as the P-47 synthetic route.

[0301]

[0302] 1) Synthesis of intermediate 1 (1-(tert-butyl) 2-methyl (S)-4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1,2-dicarboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 512 (M+H + )

[0303] 2) Synthesis of intermediate 2 (1-(tert-butyl) 2-methyl (S)-4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1,2-dicarboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 571 (M+H + )

[0304] 3) Synthesis of intermediate 3 (methyl (S)-4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-2-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 471 (M+H + )

[0305] 4) Synthesis of intermediate 4 (methyl (S)-4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(methylsulfonyl)piperazine-2-carboxylate): The intermediate 3 (1 g, 2.13 mmol) was dissolved in DCM (10 mL), and methanesulfonyl chloride (0.41 mL, 5.31 mmol) and iPr2EtN (0.89 mL, 6.38 mmol) were added, and the mixture was stirred at 0°C for 18 h. After completion of the reaction, extraction was performed using EA and H2O at room temperature. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Intermediate 4 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z549 (M+H + )

[0306] 5) P-47 ((S)-4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(methylsulfonyl)piperazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 535 (M+H + )

[0307] (20) Representative synthesis example 20

[0308] The above P-50 synthetic route is specified below.

[0309]

[0310] 1) Synthesis of intermediate 1 (tert-butyl 4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 593 (M+H + )

[0311] 2) P-50 ((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 535 (M+H + )

[0312] (21) Representative synthesis example 21

[0313] The synthetic route of P-51 is specified below. In addition, the synthesis of P-52, P-53, P-64, P-65, P-67, and P-68 was carried out using synthetic routes identical to or modified from the P-51 synthetic route.

[0314]

[0315] 1) Synthesis of intermediate 2 (4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine): Synthesized using the above synthetic method F. ESI-MS m / z 235 (M+H + )

[0316] 2) Synthesis of intermediate 3 (5-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine): Synthesized using the above synthetic method D. ESI-MS m / z 294 (M+H + )

[0317] 3) Synthesis of intermediate 4 (tert-butyl 4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 444 (M+H + )

[0318] 4) P-51 (5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 344 (M+H + )

[0319] (22) Representative synthesis example 22

[0320] The synthetic route of P-54 is specified below. In addition, the synthesis of P-59, P-61, P-64, and P-66 was carried out using the same or modified synthetic route as the P-54 synthetic route.

[0321]

[0322] 1) Synthesis of intermediate 2 (tert-butyl 1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 443 (M+H + )

[0323] 2) P-54 (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 387 (M+H + )

[0324] (23) Representative synthesis example 23

[0325] The above P-55 synthetic route is specified below. In addition, the synthesis of P-56 and P-69 was carried out using the same or modified synthetic route as the P-55 synthetic route.

[0326]

[0327] 1) Synthesis of intermediate 2 (4-(2,6-dichloro-5-fluoropyrimidin-4-yl)morpholine): Synthesized using the above synthetic method F. ESI-MS m / z 252 (M+H + )

[0328] 2) Synthesis of intermediate 3 (4-chloro-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-2'-amine) and 3-A (2-chloro-5-fluoro-6-morpholino-[4,5'-bipyrimidin]-2'-amine): Synthesized using the above synthetic method D. ESI-MS m / z 311 (M+H + )

[0329] 3) Synthesis of intermediate 4 (tert-butyl 4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)piperazine-1-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 461 (M+H + )

[0330] 4) Synthesis of P-55 (5-fluoro-4-morpholino-6-(piperazin-1-yl)-[2,5'-bipyrimidin]-2'-amine): Synthesized using the above synthetic method C. ESI-MS m / z 361 (M+H + )

[0331] (24) Representative synthesis example 24

[0332] The synthetic route of P-57 is specified below. In addition, the synthesis of P-70 and P-72 was carried out using the same or modified synthetic route as the P-57 synthetic route.

[0333]

[0334] 1) Synthesis of intermediate 1 (methyl 4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoate): Synthesized using the above synthetic method D. ESI-MS m / z 412 (M+H + )

[0335] 2) P-57 (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 398 (M+H + )

[0336] (25) Representative synthesis example 25

[0337] The synthetic route of P-27 is specified below. In addition, the synthesis of P-71 and P-73 was carried out using the same or modified synthetic route as the P-27 synthetic route.

[0338]

[0339] 1) Synthesis of intermediate 1 (methyl 4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-3-fluorobenzoate): Synthesized using the above synthetic method D. ESI-MS m / z 429 (M+H + )

[0340] 2) P-58 (4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-3-fluorobenzoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 415 (M+H + )

[0341] (26) Representative synthesis example 26

[0342] The synthetic route of P-63 is given below.

[0343]

[0344] 1) Synthesis of intermediate 2 (tert-butyl 4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazine-1-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 458 (M+H + )

[0345] 2) P-63 (5-(4-morpholino-6-(piperazin-1-yl-methyl)-1,3,5-triazin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 358 (M+H + )

[0346] (27) Representative synthesis example 27

[0347] The synthetic route of P-74 is given below.

[0348]

[0349] 1) Synthesis of intermediate 2 (N'-(-6-((dimethylamino)methylene)-7-oxo-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-N,N-dimethylformimidamide): The intermediate 1 (5 g, 29.7 mmol) was added to DMFDMA (24.8 g, 208.0 mmol), heated to 110°C, and stirred overnight. After completion of the reaction, the solid was precipitated using EA and tBuOEt at room temperature to obtain intermediate 2, which was used in the next reaction without purification. ESI-MS m / z 279 (M+H + )

[0350] 2) Synthesis of intermediate 3 (8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-amine): The intermediate 2 (6.4 g, 23.0 mmol) was dissolved in methoxy-ethanol (105 mL), and pivalimidamide hydrochloride (4.71 g, 34.5 mmol) and NaOEt (5.87 g, 86.2 mmol) were added. The mixture was heated to 120°C and stirred for 1 hour. After completion of the reaction, distilled water was added at room temperature, and the solid was precipitated and filtered to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 261 (M+H + )

[0351] 3) Synthesis of intermediate 4 (N-(8-(tert-butyl)-4,5-dihydrocyanazolo[4,5-h]quinazolin-2-yl)-1H-imidazole-1-carboxamide): The intermediate 3 (2 g, 7.7 mmol) was dissolved in DCM, DMF (25 mL, 2.5 mL), and CDI (2.8 g, 17 mmol) was slowly added at room temperature, followed by stirring for 1 hour. After completion of the reaction, the mixture was filtered at room temperature to obtain intermediate 4, which was used in the next reaction without purification. ESI-MS m / z 355 (M+H + )

[0352] 4) Synthesis of intermediate 5 ((2S,4R)-N1-(8-(tert-butyl)-4,5-dihydrocyanazolo[4,5-h]quinazolin-2-yl)-4-hydroxypyrrolidine-1,2-dicarboxamide): The intermediate 4 (980 mg, 2.77 mmol) was dissolved in DCM (10 mL), and iPr2EtN (0.96 mL, 5.53 mmol) and (2S,4R)-4-hydroxypyrrolidine-2-carboxamide (396 mg, 3.04 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with EA at room temperature, washed with saturated aqueous chloride, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain intermediate 5. ESI-MSm / z417 (M+H + )

[0353] 5) Synthesis of intermediate 6 (tert-butyl 2-(((3R,5S)-1-((8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)carbamoyl)-5-carbamoylpyrrolidin-3-yl)oxy)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 531 (M+H + )

[0354] 6) P-74 (2-(((3R,5S)-1-((8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)carbamoyl)-5-carbamoylpyrrolidin-3-yl)oxy)acetic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 475 (M+H + )

[0355] 7) P-74-A synthetic

[0356] - Synthesis of A-1 (methyl (2S, 4R)-4-hydroxypyrrolidine-2-carboxylate): Synthesized using the above synthesis method C. ESI-MS m / z 146 (M+H + )

[0357] - Synthesis of P-74-A ((2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid): The intermediate A-1 (1.2 g, 8.27 mmol) was dissolved in 7N NH3in MeOH (9.45 mL, 66.1 mmol) and stirred at 90°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain P-74-A. ESI-MS m / z 131 (M+H + )

[0358] (28) Representative synthesis example 28

[0359] The synthetic route of P-76 is given below.

[0360]

[0361] 1) Synthesis of intermediate 2 (tert-butyl 4-(3-(((3R,5S)-1-((8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)carbamoyl)-5-carbamoylpyrrolidin-3-yl)oxy)propyl)piperazine-1-carboxylate): The intermediate 1 (200 mg, 0.48 mmol) was dissolved in THF (2.5 mL), and NaH (35 mg, 1.44 mmol) was added at 0°C, followed by stirring for 15 minutes. After the reaction, tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (139 mg, 0.53 mmol) was added, the mixture was raised to room temperature, heated to 60°C, and stirred for 5 hours. After completion of the reaction, the mixture was diluted with EA and distilled water, extracted with EA, washed with saturated aqueous chloride, and dried over anhydrous sodium sulfate. After filtering, the mixture was concentrated under reduced pressure, and purified by MPLC (EA / Hx) to obtain intermediate 2. ESI-MS m / z 643 (M+H + )

[0362] 2) P-76 ((2S,4R)-N1-(8-(tert-butyl)-4,5-dihydrocyanazolo[4,5-h]quinazolin-2-yl)-4-(3-(piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxamide) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 543 (M+H + )

[0363] (29) Representative synthesis example 29

[0364] The synthetic route of P-77 is given below.

[0365]

[0366] 1) Synthesis of intermediate 2 (4-(1,3-dioxolan-2-yl)benzoic acid): p-Toluenesulfonic acid monohydrate (76.7 mg, 0.403 mmol) and glycerol (918 mg, 14.8 mmol) were added to a solution of intermediate 1 (2.01 g, 13.4 mmol) in toluene (33.6 mL). The mixture was stirred at 180°C for 7 hours using a Dean-Stark glassware. After cooling to room temperature, the resulting crystals were filtered to obtain the product. ESI-MS m / z 195 (M+H + )

[0367] 2) Synthesis of intermediate 3 ((4-(1,3-dioxolan-2-yl)phenyl)(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone): Synthesized using the above synthetic method B. ESI-MS m / z 490 (M+H + )

[0368] 3) P-77 (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzaldehyde) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 446 (M+H + )

[0369] (30) Representative synthesis example 30

[0370] The synthetic route of P-78 is given below.

[0371]

[0372] 1) Synthesis of intermediate 1 ((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(1-(hydroxymethyl)cyclopropyl)methanone): Synthesized using the above synthetic method B. ESI-MS m / z 412 (M+H + )

[0373] 2) Synthesis of P-78 (1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclopropane-1-carbaldehyde): The intermediate 1 (323 mg, 0.786 mmol) was dissolved in DCM (7.86 mL). Dess-Martin periodinane (667 mg, 1.57 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was mixed with a saturated sodium bicarbonate / sodium thiosulfate solution, and extracted with IPA / CHCl3 1:3 solvent. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. P-78 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 410 (M+H + )

[0374] (31) Representative synthesis example 31

[0375] The synthetic route of P-79 is given below.

[0376]

[0377] 1) Synthesis of intermediate 1 (tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate): DIPEA (359 mg, 2.78 mmol) was added to the reaction mixture of the above P-2 hydrochloride (324 mg, 927 mmol) dissolved in ethanol (9.3 mL), and stirred at 90°C for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain intermediate 1. ESI-MS m / z 437 (M+H + )

[0378] 2) P-79 (4-((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methyl)piperidin-4-ol) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 427 (M+H + )

[0379] (32) Representative synthesis example 32

[0380] The synthetic route of the above P-80 is specified below.

[0381]

[0382] 1) Synthesis of intermediate 1 (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)piperidine-4-carboxamide): Synthesized using the above synthetic method B. ESI-MS m / z 587 (M+H + )

[0383] 2) Synthesis of P-80 (2-(2-(2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carboxamido)ethoxy)ethoxy)ethylmethanesulfonate): The intermediate 1 (1 g, 1.70 mmol) was dissolved in DCM (9 mL), and methanesulfonyl chloride (0.26 mL, 3.41 mmol) and iPr2EtN (0.74 mL, 4.26 mmol) were added. The mixture was stirred at 0°C for 18 h. After completion of the reaction, extraction was performed using EA and H2O at room temperature. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. P-80 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z665 (M+H + )

[0384] (33) Representative synthesis example 33

[0385] The synthetic route of P-81 is given below.

[0386]

[0387] 1) Synthesis of intermediate 1 (3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)propan-1-ol): Synthesized using the above synthetic method B. ESI-MS m / z 372 (M+H + )

[0388] 2) Synthesis of P-81 (3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)propyl methanesulfonate): The intermediate 1 (1 g, 2.69 mmol) was dissolved in DCM (13 mL), and methanesulfonyl chloride (0.42 mL, 5.38 mmol) and iPr2EtN (1.17 mL, 6.73 mmol) were added, and the mixture was stirred at 0°C for 18 h. After completion of the reaction, extraction was performed using EA and H2O at room temperature. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. P-81 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 450 (M+H + )

[0389] (34) Representative synthesis example 34

[0390] The synthetic route of P-84 is given below.

[0391]

[0392] 1) Synthesis of intermediate 1 (ethyl 7-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 633 (M+H + )

[0393] 2) P-84 (7-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 605 (M+H + )

[0394] (35) Representative synthesis example 35

[0395] The synthetic route of P-85 is given below.

[0396]

[0397] 1) Synthesis of intermediate 1 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexene-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 496 (M+H + )

[0398] 2) P-85 (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 440 (M+H + )

[0399] (36) Representative synthesis example 36

[0400] The synthetic route of the above P-90 is specified below.

[0401]

[0402] 1) Synthesis of intermediate 1 (tert-butyl (4-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)phenyl)carbamate): Synthesized using the above synthetic method D. ESI-MS m / z 658 (M+H + )

[0403] 2) P-90 (N-(6-(4-aminophenyl)-3-(2-chloro-5-fluorophenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 558 (M+H + )

[0404] (37) Representative synthesis example 37

[0405] The synthetic route of P-91 is given below.

[0406]

[0407] 1) Synthesis of intermediate 1 (tert-butyl 1-(4-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)phenyl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate): Synthesized using the above synthetic method B. ESI-MS m / z 846 (M+H + )

[0408] 2) P-91 (1-(4-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)phenyl)-1-oxo-5,8,11-trioxa-2-azatetradecane-14-oic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 790 (M+H + )

[0409] (38) Representative synthesis example 38

[0410] The synthetic route of P-92 is given below.

[0411]

[0412] 1) Synthesis of intermediate 1 (tert-butyl 4-((1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)methyl)piperazine-1-carboxylate): Synthesized using the above synthetic method D. ESI-MS m / z 665 (M+H + )

[0413] 2) P-92 (N-(3-(2-chloro-5-fluorophenyl)-1-oxo-6-(piperazin-1-yl-methyl)isoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 565 (M+H + )

[0414] (39) Representative synthesis example 39

[0415] The synthetic route of P-104 is given below.

[0416]

[0417] 1) Synthesis of intermediate 2 (ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate): Intermediate 1 (4-bromo-6-chloropyridazin-3-amine) (4 g, 20 mmol) was dissolved in DMF (40 mL), ethyl 3-bromo-2-oxopropanoate (5 g, 26 mmol) was added, and the mixture was stirred at 80°C for 3 hours. After completion of the reaction, the mixture was extracted with EA and H2O at room temperature. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Intermediate 2 was obtained by purification by MPLC (EA / Hex). ESI-MS m / z 304 (M+H + )

[0418] 2) Synthesis of P-104 (6-chloro-8-morpholinoimidazo[1,2-b]pyridazine-2-carboxylic acid): Synthesized using the above synthetic method F. ESI-MS m / z 311 (M+H + )

[0419] (40) Representative synthesis example 40

[0420] The synthetic route of P-109 is given below.

[0421]

[0422] Synthesis of P-109 ((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethan-1-amine): Synthesis was performed with reference to W02024183806.

[0423] (41) Representative synthesis example 41

[0424] The synthetic route of P-113 is given below.

[0425]

[0426] 1) Synthesis of intermediate 2 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate): The intermediate 1 (500 mg, 1.21 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (857 mg, 3.64 mmol) were dissolved in toluene (8.1 mL) and ACN (4.1 mL), and AcOH (0.4 mL, 7 mmol) was added dropwise, followed by stirring at 120°C for 1 h. The organic layer, extracted with DCM and a saturated aqueous solution of NaCl, was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Intermediate 2 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z531 (M+H + )

[0427] 2) Synthesis of intermediate 3 (tert-butyl 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3,3-difluoropiperidine-1-carboxylate): The intermediate 2 (417 mg, 0.79 mmol) was dissolved in DCE (1.3 mL) and MeOH (1.3 mL), and AcOH (95 μL, 1.65 mmol) and NaCNBH3 (123 mg, 1.96 mmol) were added, and the mixture was stirred at 60°C for 2 hours. The organic layer extracted with DCM and saturated aqueous NaCl solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 3 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 533 (M+H + )

[0428] 3) P-113 (5-(7-(3,3-difluoropiperidin-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 433 (M+H + )

[0429] (42) Representative synthesis example 42

[0430] The synthetic route of P-119 is given below.

[0431]

[0432] 1) Synthesis of intermediate 1 (2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine): KOAc (1.42 g, 14.5 mmol) and B2(Pin)2 (1.35 g, 5.30 mmol) were added to a solution of 5-bromo-2-chloropyridin-3-amine (1.0 g, 4.82 mmol) in 1,4-Dioxane (16 mL), and the mixture was stirred at 100°C for 24 h. The reaction mixture was filtered through celite and concentrated under reduced pressure, extracted with DCM and H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain intermediate 1. ESI-MS m / z 255 (M+H + )

[0433] 2) Synthesis of intermediate 2 ((6-chloro-5-(N-(methylsulfonyl)methylsulfonamido)pyridin-3-yl)boronic acid): Synthesized using the above synthetic method E. ESI-MS m / z 328 (M+H + )

[0434] 3) Synthesis of intermediate 3 ((R)-3-(1-((6-bromoquinazolin-4-yl)amino)ethyl)phenol): Synthesized using the above synthetic method F. ESI-MS m / z 344 (M+H + )

[0435] 4) Synthesis of intermediate 4 ((R)-N-(2-chloro-5-(4-((1-(3-hydroxyphenyl)ethyl)amino)quinazolin-6-yl)pyridin-3-yl)methanesulfonamide): Synthesized using the above synthetic method D. ESI-MS m / z 470 (M+H + )

[0436] 5) Synthesis of intermediate 5 (tert-butyl (R)-5-(3-(1-((6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)quinazolin-4-yl)amino)ethyl)phenoxy)pentanoate): Synthesized using the above synthetic method E. ESI-MS m / z 626 (M+H + )

[0437] 6) P-119 ((R)-5-(3-(1-((6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)quinazolin-4-yl)amino)ethyl)phenoxy)pentanoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 570 (M+H + )

[0438] (43) Representative synthesis example 43

[0439] The synthetic route of P-121 is given below.

[0440]

[0441] 1) Synthesis of intermediate 2 (methyl (2S, 3R)-3-hydroxypyrrolidine-2-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 146 (M+H + )

[0442] 2) Synthesis of intermediate 3 ((3R)-3-hydroxypyrrolidine-2-carboxamide): Ammonia methanol solution (7 M, 2.55 mL, 17.8 mmol) was added to intermediate 2 (162 mg, 0.892 mmol), and stirred at 70°C for 20 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain intermediate 3. ESI-MS m / z 131 (M+H + )

[0443] 3) Synthesis of intermediate 5 ((3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-hydroxypyrrolidine-1,2-dicarboxamide): Intermediate 4 (169 mg, 0.476 mmol) was dissolved in DCM (4.7 mL) and TEA (0.13 mL), and then intermediate 3 (87 mg, 0.476 mmol) was added and stirred at room temperature for 21 h. After completion of the reaction, extraction was performed using IPA, CHCl3, and H2O at room temperature. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Intermediate 5 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 417 (M+H + )

[0444] 4) Synthesis of intermediate 6 (tert-butyl 2-(((2R,3R)-1-((8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)carbamoyl)-2-carbamoylpyrrolidin-3-yl)oxy)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 531 (M+H + )

[0445] 5) P-121 (2-(((2R,3R)-1-((8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)carbamoyl)-2-carbamoylpyrrolidin-3-yl)oxy)acetic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 475 (M+H + )

[0446] (44) Representative synthesis example 44

[0447] The synthetic route of P-125 is given below.

[0448]

[0449] P-125 (4'-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1,1'-biphenyl]-4-carbaldehyde) Synthesis: Synthesized using the above synthetic method B. ESI-MS m / z 522 (M+H + )

[0450] (45) Representative synthesis example 45

[0451] The synthetic route of P-129 is given below.

[0452]

[0453] 1) Synthesis of intermediate 1 ((1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(dimethoxymethyl)piperidin-1-yl)methanone): Synthesized using the above synthetic method B. ESI-MS m / z 597 (M+H + )

[0454] 2) P-129 (1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidine-4-carbaldehyde) Synthesis: 1,4-dioxane (2.5 mL) and H2O (1.5 mL) were added to intermediate 1 (240 mg, 0.403 mmol), followed by adding HCl(aq) (35 wt%, 0.33 mL) and stirring at 85°C for 1 h. The reaction mixture was poured into a saturated NaHCO3 aqueous solution at room temperature and extracted using IPA and CHCl3. The organic layer was washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain P-129. ESI-MS m / z 551 (M+H + )

[0455] (46) Representative synthesis example 46

[0456] The synthetic route of P-130 is specified below.

[0457]

[0458] 1) Synthesis of intermediate 2 (N6-((benzyloxy)carbonyl)-N2-(2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-lysine): Intermediate 1 (437 mg, 1.12 mmol), N6-((benzyloxy)carbonyl)-L-lysine (782 mg, 2.79 mmol), CuI (42 mg, 0.223 mmol), and K3PO4 (959 mg, 4.52 mmol) were dissolved in DMSO (3.6 mL) and stirred at 100°C for 20 h. The reaction mixture was extracted with DCM and saturated NaCl aqueous solution at room temperature. The intermediate 2 was obtained by drying over anhydrous Na2SO4 and then concentrating under reduced pressure. ESI-MSm / z592 (M+H + )

[0459] 2) Synthesis of intermediate 3 (benzyl((S)-6-amino-5-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-6-oxohexyl)carbamate): Synthesized using the above synthetic method B. ESI-MS m / z 591 (M+H + )

[0460] 3) Synthesis of intermediate 4 ((S)-6-amino-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide): Synthesized using the above synthetic method G. ESI-MS m / z 457 (M+H + )

[0461] 4) Synthesis of intermediate 5 (tert-butyl 4-(((S)-6-amino-5-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-6-oxohexyl)amino)-4-oxobutanoate): Synthesized using the above synthetic method B. ESI-MS m / z 613 (M+H + )

[0462] 5) P-130 (4-(((S)-6-amino-5-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-6-oxohexyl)amino)-4-oxobutanoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 557 (M+H + )

[0463] (47) Representative synthesis example 47

[0464] The synthetic route of P-131 is specified below. In addition, the synthesis of P-133, P-134, P-135, and P-136 was carried out using the same or modified synthetic route as the P-131 synthetic route.

[0465]

[0466] 1) Synthesis of intermediate 2 (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-ol): Synthesized using the above synthetic method D. ESI-MS m / z 428 (M+H + )

[0467] 2) Synthesis of P-131 (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl(perfluorophenyl)carbonate): To a DMSO (0.94 mL) solution of the intermediate 2 (40 mg, 0.094 mmol) was added TEA (19 mg, 0.19 mmol) and bis(perfluorophenyl)carbonate (74 mg, 0.19 mmol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed using DCM and H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. P-131 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 638 (M+H + )

[0468] (48) Representative synthesis example 48

[0469] The synthetic route of P-132 is given below.

[0470]

[0471] 1) Synthesis of intermediate 1 (tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidine-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 762 (M+H + )

[0472] 2) P-132 ((9H-fluoren-9-yl)methyl(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-4-yl)carbamate) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 662 (M+H + )

[0473] [Synthesis Example 3] Specific synthesis of HSP90 binder

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] (1) Representative synthesis example 1

[0488] The above H-3 synthetic route is specified below. In addition, the above H-4 synthesis was carried out using a synthetic route identical to or modified from the H-3 synthetic route.

[0489]

[0490] 1) Synthesis of intermediate 1 (tert-butyl 2-(4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 787 (M+H + )

[0491] 2) H-3 (2-(4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 731 (M+H + )

[0492] (2) Representative synthesis example 2

[0493] The above H-5 synthetic route is specified below. In addition, the synthesis of H-39 and H-40 was carried out using the same or modified synthetic route as the H-5 synthetic route.

[0494]

[0495] 1) Synthesis of Intermediate 2 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-vinylisoindolin-2-yl)methanone): The intermediate 1 (100 g, 180.3 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (33.3 g, 216.4 mmol), and K2CO3 (3.2 g, 29.7 mmol) were dissolved in 1,4-Dioxane (455 mL) and H2O (91 mL), and then the gas was removed by ultrasonication for 10 minutes under nitrogen. Pd(PPh3)4 (10.4 g, 9.0 mmol) was added to the reaction mixture, and the mixture was stirred and refluxed at 100°C for 4 hours. After completion of the reaction, it was cooled to room temperature, filtered with celite, and concentrated under reduced pressure. The mixture was purified by chromatography (EA / HEX) to obtain intermediate 2. ESI-MSm / z504 (M+H + )

[0496] 2) Synthesis of intermediate 3 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(1,2-dihydroxyethyl)isoindolin-2-yl)methanone): The intermediate 2 (63 g, 125.1 mmol) was dissolved in THF (333 mL) and H2O (83 mL), and N-methylmorpholine N-oxide (102.8 mL, 500.4 mmol) and OsO4 (40.7 g, 4.00 mmol) were added, and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 538 (M+H + )

[0497] 3) Synthesis of H-68 (2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindoline-5-carbaldehyde): The intermediate 3 (67 g, 124.6 mmol) and NaIO4 (53.3 g, 249.2 mmol) were dissolved in THF (470 mL) and H2O (160 mL), and stirred at room temperature for 1 hour. The reaction mixture was extracted with EA and H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The intermediate P-68 was obtained by purification by MPLC (EA / HEX). ESI-MS m / z 506 (M+H + )

[0498] 4) Synthesis of intermediate 4 (methyl 1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 633 (M+H + )

[0499] 5) Synthesis of intermediate 5 (methyl 1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 453 (M+H + )

[0500] 6) H-5 (1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 439 (M+H + )

[0501] (3) Representative synthesis example 3

[0502] The above H-6 synthetic route is specified below.

[0503]

[0504] 1) Synthesis of intermediate 1 (methyl 4-(4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butenoate): Synthesized using the above synthetic method E. ESI-MS m / z 676 (M+H + )

[0505] 2) H-6 (4-(4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butanoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 662 (M+H + )

[0506] (4) Representative synthesis example 4

[0507] The synthetic route of H-8 is specified below. In addition, the synthesis of H-16, H-18, H-19, H-28, H-31, H-33, H-38, H-44, H-45, H-47, 47-Bn, H-50, H-51, H-52, H-53, H-62, and H-77 was carried out using synthetic routes identical to or modified from the H-8 synthetic route.

[0508]

[0509] 1) Synthesis of intermediate 1 (tert-butyl 4-(4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 759 (M+H + )

[0510] 2) Synthesis of intermediate 2 (tert-butyl 4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 579 (M+H + )

[0511] 3) H-8 ((2,4-dihydroxy-5-isopropylphenyl)(5-((4-(piperidin-4-yl)piperazin-1-yl)methyl)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 479 (M+H + )

[0512] (5) Representative synthesis example 5

[0513] The synthetic route of H-9 is specified below. In addition, the synthesis of H-13 to H-15, H-20, H-22, H-27, H-29, H-36, H-42, H-64, and H-69 was carried out using synthetic routes identical to or modified from the H-9 synthetic route.

[0514]

[0515] 1) Synthesis of intermediate 2 (tert-butyl 4-(4-(methoxycarbonyl)benzyl)piperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 335 (M+H + )

[0516] 2) Synthesis of intermediate 3 (methyl 4-(piperazin-1-ylmethyl)benzoate): Synthesized using the above synthetic method C. ESI-MS m / z 235 (M+H + )

[0517] 3) Synthesis of intermediate 4 (methyl 4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)benzoate): Synthesized using the above synthetic method A. ESI-MS m / z 724 (M+H + )

[0518] 4) Synthesis of intermediate 5 (4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)benzoic acid): Synthesized using the above synthetic method C. ESI-MS m / z 710 (M+H + )

[0519] 5) H-9 (4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)benzoic acid) Synthesis: Synthesized using the above synthetic method G. ESI-MS m / z 530 (M+H + )

[0520] (6) Representative synthesis example 6

[0521] The synthetic route of H-12 is given below.

[0522]

[0523] 1) Synthesis of intermediate 1 (methyl 4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)benzoate): Synthesized using the above synthetic method A. ESI-MS m / z 558 (M+H + )

[0524] 2) H-12 (4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)benzoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 544 (M+H + )

[0525] (7) Representative synthesis example 7

[0526] The above H-24 synthetic route is specified below. In addition, the synthesis of H-25 and H-61 was carried out using synthetic routes identical to or modified from the H-24 synthetic route.

[0527]

[0528] 1) Synthesis of intermediate 1 (methyl 1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidine-4-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 564 (M+H + )

[0529] 2) H-24 (1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 550 (M+H + )

[0530] (8) Representative synthesis example 8

[0531] The above H-34 synthetic route is specified below. In addition, the above H-69 synthesis was carried out using a synthetic route identical to or modified from the H-24 synthetic route.

[0532]

[0533] 1) Synthesis of intermediate 1 (methyl 5-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)pyrazine-2-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 546 (M+H + )

[0534] 2) H-34 (5-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 532 (M+H + )

[0535] (9) Representative synthesis example 9

[0536] The synthetic route of H-35 is given below.

[0537]

[0538] 1) Synthesis of intermediate 2 (ethyl 5-(hydroxymethyl)pyrazine-2-carboxylate): The intermediate 1 (302 mg, 1.82 mmol) was dissolved in ethanol (6.1 mL) and cooled to 0°C. NaBH4 (68.9 mg, 1.82 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. Water and EA were added to the reaction mixture and washed with water, saturated NH4Cl aqueous solution, and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 2. ESI-MS m / z 183 (M+H + )

[0539] 2) Synthesis of intermediate 3 (ethyl 5-(chloromethyl)pyrazine-2-carboxylate): The intermediate 2 (97.7 mg, 0.536 mmol) was dissolved in DCM (2.7 mL) and cooled to 0°C. DIPEA (0.234 mL, 1.34 mmol) and methanesulfonyl chloride (0.083 mL, 1.1 mmol) were added to the reaction mixture and stirred at room temperature for 3 hours. Extraction was performed using saturated sodium bicarbonate and DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 3. ESI-MS m / z 201 (M+H + )

[0540] 3) Synthesis of intermediate 4 (ethyl (S)-5-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methyl)pyrazine-2-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 590 (M+H + )

[0541] 4) H-35 ((S)-5-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methyl)pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 562 (M+H + )

[0542] (10) Representative synthesis example 10

[0543] The synthetic route of H-37 is given below.

[0544]

[0545] 1) Synthesis of intermediate 2 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)methanone): The intermediate 1 (25.0 g, 44.92 mmol), B2pin2 (17.11 g, 67.39 mmol), KOAc (13.23 g, 134.8 mmol), Pd(dppf)Cl2.CH2Cl2 (1.83 g, 2.25 mmol) were dissolved in 1,4-dioxane (224 mL) and stirred at room temperature for 20 minutes under nitrogen. The reaction mixture was heated to 90°C and stirred for 3 hours. After cooling the reaction mixture to room temperature, it was passed through a silica pad to obtain intermediate 2. ESI-MSm / z604 (M+H + )

[0546] 2) Synthesis of H-75 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-hydroxyisoindolin-2-yl)methanone): The intermediate 2 (27.0 g, 44.7 mmol) was dissolved in THF (890 mL) and cooled to 0°C. 1 M aqueous sodium hydroxide solution (179 mL) was added to the reaction mixture, and 35% aqueous hydrogen peroxide was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, cooled to 0°C, and 1 M aqueous hydrochloric acid solution (179 mL) was slowly added dropwise. The reaction mixture was filtered to obtain H-75. ESI-MS m / z 494 (M+H + )

[0547] 3) Synthesis of intermediate 3 (tert-butyl 4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidine-1-carboxylate): The above H-75 (5.00 g, 10.1 mmol), PPh3 (3.51 g, 13.4 mmol), and tert-butyl 4-hydroxypiperidine-1-carboxylate (4.08 g, 20.3 mmol) were dissolved in THF (72 mL), and then cooled to 0°C. Diisopropyl azodicarboxylate (2.6 mL, 13 mmol) was slowly added dropwise to the reaction mixture, and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by normal phase chromatography to obtain intermediate 3. ESI-MS m / z 677 (M+H + )

[0548] 4) Synthesis of intermediate 4 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(piperidin-4-yloxy)isoindolin-2-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 577 (M+H + )

[0549] 5) Synthesis of intermediate 5 (tert-butyl 4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 774 (M+H + )

[0550] 6) Synthesis of intermediate 6 (tert-butyl 4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 594 (M+H + )

[0551] 7) H-37 ((2,4-dihydroxy-5-isopropylphenyl)(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 494 (M+H + )

[0552] (11) Representative synthesis example 11

[0553] The synthetic route for H-41 is specified below. In addition, the synthesis of H-48, H-59, and H-60 ​​was carried out using synthetic routes identical to or modified from the H-41 synthetic route.

[0554]

[0555] 1) Synthesis of intermediate 2 (tert-butyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 497 (M+H + )

[0556] 2) Synthesis of H-41 ((2,4-dihydroxy-5-isopropylphenyl)(5-(piperidin-4-yloxy)isoindolin-2-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 397 (M+H + )

[0557] (12) Representative synthesis example 12

[0558] The synthetic route of H-54 is specified below.

[0559]

[0560] 1) Synthesis of intermediate 2 (methyl 1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 453 (M+H + )

[0561] 2) Synthesis of intermediate 3 (methyl 1-((2-(3-formyl-2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxylate): The intermediate 2 (1 g, 2.21 mmol) was dissolved in TFA (4.4 mL), and hexamine (0.62 g, 4.42 mmol) was added. The mixture was stirred and heated at 100°C for 2 hours. After the reaction was completed, the mixture was cooled and concentrated under reduced pressure to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 481 (M+H + )

[0562] 3) Synthesis of intermediate 4 (methyl 1-((2-(4-hydroxy-7-isopropylbenzo[d]isooxazole-5-carbonyl)isoindolin-5-yl)methyl)piperidine-4-carboxylate): The intermediate 3 (940 mg, 1.96 mmol) was dissolved in acetone (20 mL), and NaN3 (191 mg, 2.93 mmol) and trifluoromethanesulfonic acid (1 mL, 11.7 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed using EA and H2O, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 4 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 478 (M+H + )

[0563] 4) H-54 (1-((2-(4-hydroxy-7-isopropylbenzo[d]isoxazole-5-carbonyl)isoindolin-5-yl)methyl)piperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 464 (M+H + )

[0564] (13) Representative synthesis example 13

[0565] The synthetic route of H-56 is given below.

[0566]

[0567] 1) Synthesis of intermediate 2 (2,4-bis(benzyloxy)-5-chlorobenzaldehyde): The intermediate 1 (0.5 g, 2.90 mmol) and K2CO3 (1.2 g, 8.69 mmol) were added to DMF (15 mL), stirred, benzyl bromide (0.8 mL, 6.37 mmol) was added, and heated at 60°C for 1 hour while stirring. After the reaction was completed, the mixture was cooled, and an excess of H2O was added to the reaction mixture, followed by stirring. The resulting solid was filtered, washed with H2O, and dried to obtain intermediate 2, which was used in the next reaction without purification. ESI-MS m / z 353 (M+H + )

[0568] 2) Synthesis of intermediate 3 (2,4-bis(benzyloxy)-5-chlorobenzoic acid): The intermediate 2 (1 g, 2.83 mmol) was dissolved in DMSO (0.8 mL), THF (8 mL), and H2O (8 mL), and then cooled. An aqueous solution of sulfamic acid (0.7 mL, 14.2 mmol) and NaClO2 (1.28 g, 14.2 mmol) in H2O (7 mL) was added to the cooled reaction mixture, and stirred at room temperature for 40 minutes. The organic layer extracted with EA and H2O was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 369 (M+H + )

[0569] 3) Synthesis of intermediate 4 ((2,4-bis(benzyloxy)-5-chlorophenyl)(5-bromoisoindolin-2-yl)methanone): Synthesized using the above synthetic method B. ESI-MS m / z 548 (M+H + )

[0570] 4) Synthesis of intermediate 5 (tert-butyl 4-((2-(2,4-bis(benzyloxy)-5-chlorobenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate): The intermediate 4 (300 mg, 0.44 mmol), potassium ((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)trifluoroborate (161 mg, 0.53 mmol), and K2CO3 (181 mg, 1.31 mmol) were dissolved in 1,4-dioxane (2 mL) and H2O (0.4 mL), and the gas was removed by sonication for 5 min under nitrogen. Pd(dppf)Cl2·DCM (35.7 mg, 0.04 mmol) was added to the reaction mixture, and the mixture was stirred at 100°C for 2 h. After the reaction was completed, it was cooled to room temperature, filtered through Celite, and washed with EA. The obtained filtrate was concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 5. ESI-MS m / z 668 (M+H + )

[0571] 5) Synthesis of intermediate 6 ((2,4-bis(benzyloxy)-5-chlorophenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone: Synthesized using the above synthetic method C. ESI-MS m / z 568 (M+H + )

[0572] 6) Synthesis of H-56 ((5-chloro-2,4-dihydroxyphenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method G. ESI-MS m / z 388 (M+H + )

[0573] (14) Representative synthesis example 14

[0574] The above H-58 synthetic route is specified below. In addition, the above H-57 synthesis was carried out using a synthetic route identical to or modified from the H-58 synthetic route.

[0575]

[0576] 1) Synthesis of intermediate 2 (tert-butyl((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)carbamate): The intermediate 1 (2 g, 3.59 mmol), potassium(((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.28 g, 5.39 mmol), and Cs2CO3 (3.51 g, 10.8 mmol) were dissolved in 1,4-dioxane (10 mL) and H2O (1 mL), and then the gas was removed by sonication under nitrogen for 5 min. Pd(OAc)2 (81 mg, 0.36 mmol) and XPhos (171 mg, 0.36 mmol) were added to the reaction mixture, and the mixture was stirred at 100°C for 1 h. After the reaction was completed, it was cooled to room temperature, filtered through Celite, and washed with EA. The obtained filtrate was concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 2. ESI-MS m / z 607 (M+H + )

[0577] 2) Synthesis of intermediate 3 ((5-(aminomethyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 327 (M+H + )

[0578] 3) Synthesis of intermediate 4 (tert-butyl 4-((diethoxyphosphoryl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)carbamoyl)phenyl)methyl)piperazine-1-carboxylate): The above A (400 mg, 0.81 mmol) was dissolved in DCE (8 mL), and then BOPCl (207 mg, 0.81 mmol) and TEA (0.6 mL, 4.06 mmol) were added and stirred for 10 minutes. Intermediate 3 (265 mg, 0.81 mmol) was added to the reaction mixture and stirred for 1 hour. After completion of the reaction, the organic layer extracted with DCM and saturated aqueous NaHCO3 solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 4 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z765 (M+H + )

[0579] 4) H-58 (Diethyl((4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)carbamoyl)phenyl)(piperazin-1-yl)methyl)phosphonate) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 665 (M+H + )

[0580] 5) Synthesis of A-1 (tert-butyl 4-((diethoxyphosphoryl)(4-(methoxycarbonyl)phenyl)methyl)piperazine-1-carboxylate): After dissolving the above A-2 (1.5 g, 9.14 mmol) in DCM (1.8 mL), Mg(ClO4)2 (0.10 g, 0.46 mmol) was added, and the mixture was stirred for 10 minutes. tert-Butyl piperazine-1-carboxylate (1.7 g, 9.14 mmol) and P(OEt)3 (2.4 mL, 13.7 mmol) were added, and the mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, quenched with H2O, and the organic layer extracted with EA was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. A-1 was obtained by purification by MPLC (EA / Hex). ESI-MSm / z471 (M+H + )

[0581] 6) Synthesis of A (4-((4-(tert-butoxycarbonyl)piperazin-1-yl)(diethoxyphosphoryl)methyl)benzoic acid): Synthesized using the above synthetic method C. ESI-MS m / z 457 (M+H + )

[0582] (15) Representative synthesis example 15

[0583] The synthetic route of H-65 is given below.

[0584]

[0585] 1) Synthesis of intermediate 2 (methyl 4-(oxiran-2-yl)benzoate): Trimethylsulfoxonium iodide (3.49 g, 15.8 mmol) and t-BuOK (1.64 g, 14.6 mmol) were dissolved in DMSO (20 mL) and stirred at room temperature for 30 minutes. A solution of intermediate 1 (2.00 g, 12.2 mmol) dissolved in DMSO (4 mL) was slowly added dropwise to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was mixed with ice and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Intermediate 2 was obtained through normal phase chromatography.

[0586] 2) Synthesis of intermediate 3 (methyl 4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-1-hydroxyethyl)benzoate): The intermediate 2 (100 mg, 0.561 mmol) and H-1 hydrochloride (267 mg, 0.617 mmol) were dissolved in ethanol (2.8 mL), and DIPEA (0.29 mL, 1.68 mmol) was added. The mixture was stirred at 80°C for 6 hours. The reaction mixture was concentrated under reduced pressure and then purified by normal phase chromatography to obtain intermediate 3. ESI-MS m / z 574 (M+H + )

[0587] 3) H-65 (4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-1-hydroxyethyl)benzoic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 560 (M+H + )

[0588] (16) Representative synthesis example 16

[0589] The synthetic route of H-66 is given below.

[0590]

[0591] 1) Synthesis of intermediate 2 (methyl (S)-5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylate): To the reaction mixture of the above H-45 hydrochloride (194 mg, 0.421 mmol) dissolved in DMF (2.1 mL), DIPEA (0.22 mL, 1.3 mmol) and methyl 5-bromopyrazine-2-carboxylate (100 mg, 0.463 mmol) were added and stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by normal phase chromatography to obtain intermediate 2. ESI-MS m / z 562 (M+H + )

[0592] 2) H-66 ((S)-5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 548 (M+H + )

[0593] (17) Representative synthesis example 17

[0594] The above H-67 synthetic route is specified below. In addition, the above H-70 synthesis was carried out using a synthetic route identical to or modified from the H-67 synthetic route.

[0595]

[0596] 1) Synthesis of intermediate 2 (tert-butyl 4-((4-(methoxycarbonyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 324 (M+H+)

[0597] 2) Synthesis of intermediate 3 (methyl 1-(piperidin-4-ylmethyl)-1H-pyrazole-4-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 224 (M+H + )

[0598] 3) Synthesis of intermediate 4 (methyl 1-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-1H-pyrazole-4-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 713 (M+H + )

[0599] 4) Synthesis of intermediate 5 (methyl 1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-1H-pyrazole-4-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 533 (M+H + )

[0600] 5) H-67 (1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-1H-pyrazole-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 519 (M+H + )

[0601] (18) Representative synthesis example 18

[0602] The above H-71 synthetic route is specified below. In addition, the above H-72 synthesis was carried out using a synthetic route identical to or modified from the H-71 synthetic route.

[0603]

[0604] 1) Synthesis of intermediate 1 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(((2-(2-methoxyethoxy)ethyl)amino)methyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method A. ESI-MS m / z 609 (M+H + )

[0605] 2) Synthesis of intermediate 2 (tert-butyl 4-(((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 792 (M+H + )

[0606] 3) Synthesis of intermediate 3 (tert-butyl 4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 612 (M+H + )

[0607] 4) H-71 ((2,4-dihydroxy-5-isopropylphenyl)(5-(((2-(2-methoxyethoxy)ethyl)(piperidin-4-yl)amino)methyl)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 512 (M+H + )

[0608] (19) Representative synthesis example 19

[0609] The above H-73 synthetic route is specified below. In addition, the above H-74 synthesis was carried out using a synthetic route identical to or modified from the H-73 synthetic route.

[0610]

[0611] 1) Synthesis of intermediate 1 ((5-((1,4-dioxa-8-azaspiro[4.5]decan-8-yl)methyl)isoindolin-2-yl)(2,4-bis(benzyloxy)-5-isopropylphenyl)methanone): Synthesized using the above synthetic method A. ESI-MS m / z 633 (M+H + )

[0612] 2) Synthesis of intermediate 2 (1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-one): Synthesized using the above synthetic method C. ESI-MS m / z 589 (M+H + )

[0613] 3) Synthesis of intermediate 3 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-((4-((2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method A. ESI-MS m / z 692 (M+H + )

[0614] 4) H-73 ((2,4-dihydroxy-5-isopropylphenyl)(5-((4-((2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methyl)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 512 (M+H + )

[0615] (20) Representative synthesis example 20

[0616] The synthetic route of H-76 ((5-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)isoindolin-2-yl)(2,4-bis(benzyloxy)-5-isopropylphenyl)methanone) is given below.

[0617]

[0618] : It was synthesized using the above synthetic method A. ESI-MSm / z752 (M+H + )

[0619] (21) Representative synthesis example 21

[0620] The above H-10 synthetic route is specified below.

[0621]

[0622] 1) Synthesis of intermediate 1 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-((4-(dimethoxymethyl)piperidin-1-yl)methyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method A. ESI-MS m / z 649 (M+H + )

[0623] 2) Synthesis of intermediate 2 (1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbaldehyde): Synthesized using the above synthetic method C. ESI-MS m / z 603 (M+H + )

[0624] 3) Synthesis of intermediate 3 (methyl 1-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)azetidine-3-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 702 (M+H + )

[0625] 4) Synthesis of intermediate 4 (methyl 1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)azetidine-3-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 522 (M+H + )

[0626] 5) H-10 (1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)azetidine-3-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 508 (M+H + )

[0627] (22) Representative synthesis example 22

[0628] The synthetic route of the above H-11 is specified below.

[0629]

[0630] 1) Synthesis of intermediate 2 (3,3'-(hydroxyphosphoryl)dipropionic acid): A mixture of NH4H2PO2 (2.5 g, 30 mmol) and hexamethyldisilazane (4.9 g, 30 mmol) was stirred at 120°C for 2 h. DCM (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. Ethyl acrylate (6.1 g, 61 mmol) was slowly added dropwise to the reaction mixture at 0°C, and the reaction mixture was stirred at room temperature for 15 h. After concentrating the reaction mixture under reduced pressure, HCl(aq) (20 mL) was added to the intermediate purified by reverse phase chromatography to obtain intermediate 2. ESI-MS m / z 211 (M+H + )

[0631] 2) H-11 (3-((3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)(hydroxy)phosphoryl)propanoic acid) Synthesis: Synthesized using the above synthetic method B. ESI-MS m / z 588 (M+H + )

[0632] (23) Representative synthesis example 23

[0633] The synthetic route of the above H-17 is specified below.

[0634]

[0635] 1) Synthesis of intermediate 2 (2-(4-amino-1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid): The intermediate 1 tert-butyl 4-oxopiperidine-1-carboxylate (4.4 g, 22 mmol), malonic acid (2.5 g, 24 mmol), and ammonium acetate (3.9 g, 51 mmol) were dissolved in n-butanol (55 mL) and heated at 120°C for 2 hours. After cooling to room temperature and filtering, intermediate 2 was obtained. ESI-MS m / z 259 (M+H + )

[0636] 2) Synthesis of intermediate 3 (2-(4-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid): The intermediate 2 (2.1 g, 8.2 mmol) and Na2CO3 (2.6 g, 25 mmol) were dissolved in distilled water (31 mL), and Fmoc-OSu (4.2 g, 12 mmol) dissolved in 1,4-dioxane was added, and stirred at room temperature for 12 hours. After concentration under reduced pressure to remove some of 1,4-dioxane, the aqueous layer was acidified with HCl and extracted with EA. After drying over anhydrous sodium sulfate, it was filtered and concentrated under reduced pressure. The intermediate 3 was obtained by purification by normal phase chromatography. ESI-MS m / z 481 (M+H + )

[0637] 3) Synthesis of intermediate 4 (tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidine-1-carboxylate): Synthesized using the above synthetic method B. ESI-MS m / z 941 (M+H + )

[0638] 4) H-17 ((9H-fluoren-9-yl)methyl (4-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)carbamate) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 841 (M+H + )

[0639] (24) Representative synthesis example 24

[0640] The synthetic route of the above H-80 is specified below.

[0641]

[0642] 1) Synthesis of intermediate 2 (ethyl (R)-3-(2-bromo-4-fluorophenyl)-3-((3-((tert-butoxycarbonyl)amino)propyl)amino)propanoate): Synthesized using the above synthetic method A. ESI-MS m / z 447 (M+H + )

[0643] 2) Synthesis of intermediate 3 (ethyl (R)-3-(2-bromo-4-fluorophenyl)-3-(N-(3-((tert-butoxycarbonyl)amino)propyl)-3-oxobutanamido)propanoate): Synthesized using the above synthetic method B. ESI-MS m / z 531 (M+H + )

[0644] 3) Synthesis of intermediate 4 (tert-butyl(3-((6R)-3-acetyl-6-(2-bromo-4-fluorophenyl)-2,4-dioxopiperidin-1-yl)propyl)carbamate): Intermediate 3 (510 mg, 0.960 mmol) was placed in a glass pressure vessel, dissolved in 19 mL of methanol, and sodium methoxide (156 mg, 2.88 mmol) was added, and stirred at 100°C for 1 hour. The mixture was extracted with saturated aqueous ammonium chloride and DCM. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain intermediate 4. ESI-MS m / z 485 (M+H + )

[0645] 4) Synthesis of intermediate 5 (tert-butyl (R)-(3-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propyl)carbamate): Intermediate 4 (347 mg, 0.715 mmol) was dissolved in ethanol (7.1 mL) in a glass pressure vessel, and N-carbamimidoylacetamide (108 mg, 1.07 mmol) and pyrrolidine (56 mg, 0.79 mmol) were added, and the mixture was stirred at 110°C for 12 h. The reaction mixture was concentrated under reduced pressure. Intermediate 5 was obtained by purification by MPLC (EA / Hex). ESI-MS m / z 508 (M+H+ )

[0646] 5) Synthesis of intermediate 6 (tert-butyl (R)-(3-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propyl)carbamate): Synthesized using the above synthetic method D. ESI-MS m / z 537 (M+H + )

[0647] 6) H-80 ((R)-2-amino-6-(3-aminopropyl)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 437 (M+H + )

[0648] (25) Representative synthesis example 25

[0649] The synthetic route of the above H-86 is specified below.

[0650]

[0651] 1) Synthesis of intermediate 1 ((E)-(2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(2-ethoxyvinyl)isoindolin-2-yl)methanone): H-97 (8.745 g, 15.71 mmol), Pd(PPh3)2Cl2 (1.102 g, 1.571 mmol), LiCl (1.998 g, 47.14 mmol) were dissolved in DMF (39 mL), and (Z)-tributyl(2-ethoxyvinyl)stannane (6.243 g, 17.29 mmol) was added, followed by stirring at 100°C for 1 h. After completion of the reaction, extraction was performed using EA and H2O. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Intermediate 1 was obtained by purification by MPLC (EA / Hex). ESI-MSm / z548 (M+H + )

[0652] 2) Synthesis of intermediate 2 (2-(2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)acetaldehyde): The intermediate 1 (10.59 g, 19.34 mmol) was dissolved in THF (96 mL) and H2O (80 mL), and HCl(aq) (35 wt%, 16 mL) was added, followed by stirring at 70°C for 4 hours. After completion of the reaction, the mixture was extracted using DCM and saturated NaHCO3 aqueous solution. The organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Intermediate 2 was obtained by purification by MPLC (EA / Hex). ESI-MS m / z 520 (M+H + )

[0653] 3) Synthesis of intermediate 3 (tert-butyl 4-(1-(2-(2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 773 (M+H + )

[0654] 4) Synthesis of intermediate 4 (tert-butyl 4-(1-(2-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 593 (M+H + )

[0655] 5) H-86 ((2,4-dihydroxy-5-isopropylphenyl)(5-(2-(4-(piperazin-1-yl)piperidin-1-yl)ethyl)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 493 (M+H + )

[0656] (26) Representative synthesis example 26

[0657] The synthetic route of the above H-88 is specified below.

[0658]

[0659] 1) Synthesis of intermediate 2 (tert-butyl 4-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 774 (M+H + )

[0660] 2) Synthesis of intermediate 3 (tert-butyl 4-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 594 (M+H + )

[0661] 3) H-88 ((2,4-dihydroxy-5-isopropylphenyl)(5-((4-(piperidin-4-yloxy)piperidin-1-yl)methyl)isoindolin-2-yl)methanone) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 494 (M+H + )

[0662] (27) Representative synthesis example 27

[0663] The synthetic route of the above H-89 is specified below.

[0664]

[0665] 1) Synthesis of intermediate 2 (ethyl (E)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-4-oxobut-2-enoate): Synthesized using the above synthetic method B. ESI-MS m / z 522 (M+H + )

[0666] 2) Synthesis of H-89 ((E)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-4-oxobut-2-enoic acid): Synthesized using the above synthetic method C. ESI-MS m / z 494 (M+H + )

[0667] (28) Representative synthesis example 28

[0668] The synthetic route of the above H-91 is specified below.

[0669]

[0670] 1) Synthesis of intermediate 2 (tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 432 (M+H + )

[0671] 2) Synthesis of intermediate 3 (tert-butyl 3-oxo-4-(piperidin-4-ylmethyl)piperazine-1-carboxylate): The intermediate 2 (900 mg, 2.09 mmol) and 10% Pd / C (20 wt%) were dissolved in MeOH (10.4 mL) and then, after vacuum decompression, air was removed using a H2 balloon (repeated three times), and stirred for 4 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. Afterwards, it was extracted using DCM and H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain intermediate 3. ESI-MS m / z 298 (M+H + )

[0672] 3) Synthesis of intermediate 4 (tert-butyl 4-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 787 (M+H + )

[0673] 4) Synthesis of intermediate 5 (tert-butyl 4-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 607 (M+H + )

[0674] 5) H-91 (1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 507 (M+H + )

[0675] (29) Representative synthesis example 29

[0676] The synthetic route of the above H-92 is specified below.

[0677]

[0678] 1) Synthesis of intermediate 1 (benzyl 4-(2-(((4-nitrophenyl)sulfonyl)oxy)ethyl)piperidine-1-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 449 (M+H + )

[0679] 2) Synthesis of intermediate 2 (tert-butyl 4-(2-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 446 (M+H + )

[0680] 3) Synthesis of intermediate 3 (tert-butyl 3-oxo-4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate): The intermediate 2 (900 mg, 2.02 mmol) and 10% Pd / C (20 wt%) were dissolved in MeOH (15.5 mL) and then stirred for 4 hours after removing air using a H2 balloon (repeated 3 times) under reduced pressure in a vacuum. The reaction mixture was filtered through Celite and concentrated under reduced pressure. Afterwards, it was extracted using DCM and H2O, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain intermediate 3. ESI-MS m / z 312 (M+H + )

[0681] 4) Synthesis of intermediate 4 (tert-butyl 4-(2-(1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)ethyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 801 (M+H + )

[0682] 5) Synthesis of intermediate 5 (tert-butyl 4-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)ethyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 621 (M+H + )

[0683] 6) H-92 (1-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)ethyl)piperazin-2-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 521 (M+H + )

[0684] (30) Representative synthesis example 30

[0685] The synthetic route of the above H-94 is specified below.

[0686]

[0687] 1) Synthesis of intermediate 2 (methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 338 (M+H + )

[0688] 2) Synthesis of intermediate 3 (methyl 5-(piperidin-4-yloxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 238 (M+H + )

[0689] 3) Synthesis of intermediate 4 (methyl 5-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 727 (M+H + )

[0690] 4) H-94 (5-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method G. ESI-MS m / z 533 (M+H + )

[0691] (31) Representative synthesis example 31

[0692] The synthetic route of the above H-96 is specified below.

[0693]

[0694] 1) Synthesis of intermediate 1 (tert-butyl 4-(1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 759 (M+H + )

[0695] 2) Synthesis of intermediate 2 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-((4-(piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 659 (M+H + )

[0696] 3) Synthesis of intermediate 3 (tert-butyl 2-(4-(1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)acetate): Synthesized using the above synthetic method E. ESI-MS m / z 773 (M+H + )

[0697] 4) Synthesis of intermediate 4 (tert-butyl 2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)acetate): Synthesized using the above synthetic method G. ESI-MS m / z 593 (M+H + )

[0698] 5) H-96 ((2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)acetic acid)) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 537 (M+H + )

[0699] (32) Representative synthesis example 32

[0700] The synthetic route of the above H-100 is specified below.

[0701]

[0702] 1) Synthesis of intermediate 2 (2-fluoro-4-hydrazinylbenzonitrile): The intermediate 1 (1.0 g, 7.19 mmol) was dissolved in MeOH (10 mL), and hydrazine hydrate (1.7 mL, 35.9 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. After concentration, the organic layer extracted with EA and H2O was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 2, which was used in the next reaction without purification. ESI-MS m / z 152 (M+H + )

[0703] 2) Synthesis of intermediate 3 (2-fluoro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzonitrile): The intermediate 2 (1.58 g, 10.45 mmol) and 2-acetyl-5,5-dimethylcyclohexane-1,3-dione (1.91 g, 10.45 mmol) were dissolved in EtOH (10.5 mL), AcOH (898 μL, 15.68 mmol) was added, and the mixture was stirred and heated at 80°C for 16 h. After completion of the reaction, the organic layer extracted with DCM and saturated aqueous NaHCO3 was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 3 was obtained by purification by MPLC (EA / Hx). ESI-MS m / z 298 (M+H + )

[0704] 3) Synthesis of intermediate 4 (2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzonitrile): The intermediate 3 (1.36 g, 2.96 mmol) and (1r,4r)-4-aminocyclohexan-1-ol hydrochloride (1.35 g, 8.89 mmol) were dissolved in DMSO, and DIPEA (2.6 mL, 14.8 mmol) was added and heated at 90°C for 16 h. After completion of the reaction, the organic layer was extracted with EA and a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 4 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z393 (M+H + )

[0705] 4) Synthesis of H-100 (2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide): The intermediate 4 (1.0 g, 2.65 mmol) and KOH (74 mg, 1.32 mmol) were dissolved in DMSO (3.5 mL) and EtOH (14.1 mL), and then cooled to 0°C. Aqueous hydrogen peroxide solution (3 mL, 26.5 mmol) was slowly added dropwise, and stirred at room temperature for 30 minutes. The organic layer extracted with EA and H2O was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain H-100, which was used in the next reaction without purification. ESI-MS m / z 411 (M+H + )

[0706] (33) Representative synthesis example 33

[0707] The synthetic route of the above H-101 is specified below.

[0708]

[0709] 1) Synthesis of intermediate 1 (tert-butyl 4-(4-formylphenyl)-3-oxopiperazine-1-carboxylate): 4-Bromobenzaldehyde (3.00 g, 16.2 mmol) was dissolved in 1,4-dioxane (54 mL), and tert-butyl 3-oxopiperazine-1-carboxylate (3.90 g, 19.5 mmol) and Cs2CO3 (10.6 g, 32.4 mmol) were added. The gas inside the solution was removed using a nitrogen balloon and an ultrasonic cleaner for 15 minutes. Xantphos (1.88 g, 3.24 mmol) and Pd2(dba)3 (1.48 g, 1.62 mmol) were added to the reaction mixture, and the mixture was stirred at 100°C for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The mixture was purified by MPLC (MeOH / DCM) to obtain intermediate 1. ESI-MS m / z 305 (M+H + )

[0710] 2) Synthesis of intermediate 2 (tert-butyl 4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)-3-oxopiperazine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 684 (M+H + )

[0711] 3) H-101 (1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)piperazin-2-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 584 (M+H + )

[0712] (34) Representative synthesis example 34

[0713] The synthetic route of the above H-102 is specified below.

[0714]

[0715] 1) Synthesis of intermediate 1 (3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzonitrile): Synthesized using the above synthetic method F. ESI-MS m / z 565 (M+H + )

[0716] 2) Synthesis of H-102 (3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzoic acid): After dissolving the intermediate 1 (287 mg, 0.508 mmol) in 1,4-Dioxane / water (3.39 mL / 1.69 mL), NaOH (203 mg, 5.08 mmol) was added, and the mixture was stirred at 100°C for 24 hours. The reaction mixture was extracted using DCM and 10% HCl aqueous solution, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain H-102. ESI-MS m / z 584 (M+H + )

[0717] (35) Representative synthesis example 35

[0718] The synthetic route of the above H-106 is specified below.

[0719]

[0720] 1) Synthesis of intermediate 2 (2,6-difluoro-4-hydrazinylbenzonitrile): To a solution of 2,4,6-trifluorobenzonitrile (1) (5 g, 31.8 mmol, 1 equiv.) in 50 mL of ethanol was heated to 60°C, and then hydrazine hydrate (50–60% solution) (3.4 g, 63.6 mmol, approximately 2 equiv.) was added. When (1) was consumed, the solvent was evaporated from the reaction mixture under vacuum. To the remaining white semi-solid, 50 mL of water was added, and the organic matter was extracted with EA (3 × 50 mL). The combined organic layers were combined and washed with saturated aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Approximately 6.3 g of a white mixture was obtained, which was used in the next reaction without further purification. ESI-MS m / z 170 (M+H + )

[0721] 2) Synthesis of intermediate 3 (2,6-difluoro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzonitrile): The intermediate 2 obtained above (1.05 g, 6.21 mmol, 1 equiv) was suspended in 100 mL of ethanol in a sealed reaction vessel with a capacity of 250 mL. Then, 2-acetyldimedon (2.83 g, 15.52 mmol, 2.5 equiv), an orange oil, was added to the reaction vessel, and the reaction vessel was sealed and heated at 100 °C for 6 h. The reaction vessel was cooled to room temperature, and the ethanol was removed under vacuum, and the remaining material was extracted with EA (3 × 50 mL) and water (100 mL). The organic layers were combined and washed with 100 mL of a saturated NaCl aqueous solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, adsorbed onto silica, and purified by MPLC (Hx / EA, 6:4) to obtain intermediate 3 (0.98 g, 50%) as a pale yellow solid. ESI-MS m / z 316 (M+H + )

[0722] 3) Synthesis of intermediate 4 (8-fluoro-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)isoquinolin-1(2H)-one)

[0723] i) A solution of benzonitrile 2 (322 mg, 1.02 mmol, 1 equiv) dissolved in 3 mL of DMF was placed in a 10 mL round-bottomed flask, and the desired β-ketoethyl ester (192 mg, 1.23 mmol, 1.2 equiv) and potassium carbonate (169 mg, 1.23 mmol, 1.2 equiv) were added, and the mixture was stirred at 70°C until compound 2 was consumed. After completion of the reaction, the mixture was acidified to pH 5 with 1 N HCl aqueous solution. Subsequently, 10 mL of a saturated NH4Cl solution was added, and extraction was performed with EA (3 × 10 mL). The combined organic layers were washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was adsorbed onto silica and purified by MPLC (Hx / EA, 3:2).

[0724] ii) The obtained material (approximately 280 mg) was placed in a sealed reaction vessel with a capacity of 40 mL, and 1.3 mL of sulfuric acid (36 N), 11.33 mL of acetic acid, and 0.7 mL of water were added. The vessel was sealed and heated at 140°C for 12 hours. The reaction mixture was added to 100 mL of water to stop the reaction. The precipitated solid was vacuum-filtered to obtain a brown solid cake, which was dried, dissolved in EA, and further purified by adsorption onto silica. The product was purified by MPLC (Hx / EA, 5:5) to isolate intermediate 4 (0.11 g, 26%) as a white solid. ESI-MS m / z 382 (M+H + )

[0725] 4) Synthesis of intermediate 5 (8-(((1r,4r)-4-hydroxycyclohexyl)amino)-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)isoquinolin-1(2H)-one): A solution of intermediate 4 (100 mg 0.26 mmol, 1 equiv) dissolved in 1.5 mL of DMSO was placed in an 8 mL sealed reaction vessel. Trans-4-aminocyclohexanol (119 mg, 0.79 mmol, 3 equiv) was added, followed by diisopropylethylamine (DIPEA) (102 mg, 0.79 mmol, 3 equiv). The reaction vessel was sealed, heated at 120 °C for 12 h, cooled, and water (25 mL) was added. The aqueous layer was extracted with EA (25 mL × 3). The combined organic layers were washed with saturated aqueous NaCl solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by MPLC (MeOH / DCM 4:96) to obtain intermediate 5 (70 mg, 55%) as a yellow solid. ESI-MS m / z 477 (M+H + )

[0726] 5) Synthesis of H-106 (4-nitrophenyl((1r,4r)-4-((1-oxo-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-1,2-dihydroisoquinolin-8-yl)amino)cyclohexyl)carbonate): A solution of intermediate 5 (50 mg 0.1 mmol, 1 equiv) dissolved in 1.0 mL of DMSO was placed in an 8 mL sealed reaction vessel. Pyridine (170 mg, 2.1 mmol, 20 equiv) was added, followed by 4-nitrophenyl carbonochloridate (32 mg, 0.16 mmol, 1.5 equiv). The reaction vessel was sealed and heated at 70°C for 12 h, cooled, and water (25 mL) was added. The aqueous layer was extracted with EA (25 mL × 3). The combined organic layers were washed with saturated NaCl aqueous solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (MeOH / DCM 5:95) to obtain H-106 (33 mg, 50%). ESI-MS m / z 642 (M+H + )

[0727] (36) Representative synthesis example 36

[0728] The synthetic route of the above H-108 is specified below.

[0729]

[0730] 1) Synthesis of intermediate 2 (methyl 1-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)piperidine-4-carboxylate): Synthesized using the above synthetic method F. ESI-MS m / z 337 (M+H + )

[0731] 2) Synthesis of intermediate 3 (1-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid): Synthesized using the above synthetic method C. ESI-MS m / z 323 (M+H + )

[0732] 3) Synthesis of intermediate 4 (tert-butyl (2-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-5-yl)carbamate): Synthesized using the above synthetic method B. ESI-MS m / z 700 (M+H + )

[0733] 4) Synthesis of intermediate 5 ((1-(5-aminopyrimidin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 600 (M+H + )

[0734] 5) H-108 (phenyl(2-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-5-yl)carbamate) Synthesis: The intermediate 5 (105 mg, 0.175 mmol) and NaHCO3 (73 mg, 0.878 mmol) were dissolved in THF (1.7 mL), and phenyl carbonochloridate (28 mg, 0.184 mmol) was slowly added dropwise at 0°C, and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain H-108. ESI-MS m / z 720 (M+H + )

[0735] (37) Representative synthesis example 37

[0736] The synthetic route of the above H-109 is specified below.

[0737]

[0738] 1) Synthesis of intermediate 2 (methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 352 (M+H + )

[0739] 2) Synthesis of intermediate 3 (methyl 5-(piperidin-4-ylmethoxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 252 (M+H + )

[0740] 3) Synthesis of intermediate 4 (methyl 5-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methoxy)pyrazine-2-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 741 (M+H + )

[0741] 4) H-109 (5-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methoxy)pyrazine-2-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 727 (M+H + )

[0742] (38) Representative synthesis example 38

[0743] The synthetic route of the above H-110 is specified below.

[0744]

[0745] 1) Synthesis of intermediate 2 (methyl(1r,4r)-4-(((5-bromopyrazin-2-yl)oxy)methyl)cyclohexane-1-carboxylate): Intermediate 1 (1.29 g, 7.37 mmol) and methyl(1r,4r)-4-(hydroxymethyl)cyclohexane-1-carboxylate (1.27 g, 7.37 mmol) were dissolved in THF, and triphenylphosphine (3.87 g, 14.7 mmol) and di-tert-butyl azodicarboxylate (3.40 g, 14.7 mmol) were added, followed by stirring at room temperature for 30 minutes. After completion of the reaction, extraction was performed using EA and H2O. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by MPLC (EA / Hex) to obtain intermediate 2. ESI-MS m / z 329 (M+H + )

[0746] 2) Synthesis of intermediate 3 (tert-butyl 4-(5-(((1r,4r)-4-(methoxycarbonyl)cyclohexyl)methoxy)pyrazin-2-yl)piperazine-1-carboxylate): Intermediate 2 (513 mg, 1.56 mmol), tert-butyl piperazine-1-carboxylate (290 mg, 1.56 mmol), XantPhos (54 mg, 0.093 mmol), sodium butoxide (225 mg, 2.34 mmol), Pd2(dba)3 (42 mg, 0.047 mmol) were dissolved in toluene (4.8 mL) and stirred at 100°C for 2 h. After completion of the reaction, extraction was performed using EA and H2O. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by MPLC (EA / Hex) to obtain intermediate 3. ESI-MS m / z 435 (M+H + )

[0747] 3) Synthesis of intermediate 4 (methyl(1r,4r)-4-(((5-(piperazin-1-yl)pyrazin-2-yl)oxy)methyl)cyclohexane-1-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 335 (M+H + )

[0748] 4) Synthesis of intermediate 5 (methyl(1r,4r)-4-(((5-(4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pyrazin-2-yl)oxy)methyl)cyclohexane-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 824 (M+H + )

[0749] 5) H-110 ((1r,4r)-4-(((5-(4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pyrazin-2-yl)oxy)methyl)cyclohexane-1-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 810 (M+H + )

[0750] (39) Representative synthesis example 39

[0751] The synthetic route of the above H-111 is specified below.

[0752]

[0753] 1) Synthesis of intermediate 2 (tert-butyl 3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate): Synthesized using the above synthetic method E. ESI-MS m / z 274 (M+H + )

[0754] 2) Synthesis of intermediate 3 (ethyl 2-(pyrrolidin-3-yloxy)acetate): Synthesized using the above synthetic method C. ESI-MS m / z 174 (M+H + )

[0755] 3) Synthesis of intermediate 4 (ethyl 2-((1-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)oxy)acetate): Synthesized using the above synthetic method F. ESI-MS m / z 367 (M+H + )

[0756] 4) Synthesis of intermediate 5 (2-((1-(5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)pyrrolidin-3-yl)oxy)acetic acid): Synthesized using the above synthetic method C. ESI-MS m / z 339 (M+H + )

[0757] 5) Intermediate 6 (tert-butyl (2-(3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidin-1-yl)pyrimidin-5-yl)carbamate) Synthesis: Synthesized using the above synthetic method B. ESI-MS m / z 813 (M+H + )

[0758] 6) Intermediate 7 (2-((1-(5-aminopyrimidin-2-yl)pyrrolidin-3-yl)oxy)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 713 (M+H + )

[0759] 7) H-111 (Phenyl (2-(3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidin-1-yl)pyrimidin-5-yl)carbamate) Synthesis: Intermediate 7 (103 mg, 0.145 mmol) and NaHCO3 (61 mg, 0.73 mmol) were dissolved in THF (1.4 mL), and phenyl carbonochloridate (24 mg, 0.15 mmol) was slowly added dropwise at 0°C, followed by stirring at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain H-111. ESI-MSm / z833 (M+H + )

[0760] (40) Representative synthesis example 40

[0761] The synthetic route of the above H-112 is specified below.

[0762]

[0763] 1) Synthesis of intermediate 1 (tert-butyl 4-(4-(1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 842 (M+H + )

[0764] 2) Synthesis of intermediate 2 (tert-butyl 4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidine-1-carboxylate): Synthesized using the above synthetic method G. ESI-MS m / z 662 (M+H + )

[0765] 3) Synthesis of intermediate 3 ((2,4-dihydroxy-5-isopropylphenyl)(5-((4-(4-(piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)methanone): Synthesized using the above synthetic method C. ESI-MS m / z 562 (M+H + )

[0766] 4) Synthesis of intermediate 5 (methyl 4-((5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)amino)butanoate): Synthesized using the above synthetic method F. ESI-MS m / z 311 (M+H + )

[0767] 5) Synthesis of intermediate 6 (4-((5-((tert-butoxycarbonyl)amino)pyrimidin-2-yl)amino)butanoic acid): Synthesized using the above synthetic method C. ESI-MS m / z 297 (M+H + )

[0768] 6) Intermediate 7 (tert-butyl (2-((4-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)pyrimidin-5-yl)carbamate) Synthesis: Synthesized using the above synthetic method B. ESI-MS m / z 840 (M+H + )

[0769] 7) Intermediate 8 (4-((5-aminopyrimidin-2-yl)amino)-1-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)butan-1-one) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 740 (M+H + )

[0770] 8) H-112 (Phenyl (2-((4-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)pyrimidin-5-yl)carbamate) Synthesis: Intermediate 8 (31 mg, 0.042 mmol) and NaHCO3 (21 mg, 0.25 mmol) were dissolved in THF (0.4 mL), and phenyl carbonochloridate (8 mg, 0.051 mmol) was slowly added dropwise at 0°C, and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain H-112. ESI-MSm / z860 (M+H + )

[0771] (41) Representative synthesis example 41

[0772] The synthetic route of the above H-113 is specified below.

[0773]

[0774] 1) Synthesis of intermediate 2 (methyl 1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate): The intermediate 1 (1.0 g, 6.53 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.72 g, 9.79 mmol), and K2CO3 (2.71 g, 19.6 mmol) were dissolved in DMF (65 mL), and stirred at 80°C for 2 hours. The organic layer extracted with EA and saturated aqueous NaCl solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 2 was obtained by purification by MPLC (EA / Hx). ESI-MS m / z 351 (M+H + )

[0775] 2) Synthesis of intermediate 3 (methyl 2-oxo-1-(piperidin-4-ylmethyl)-1,2-dihydropyridine-4-carboxylate): Synthesized using the above synthetic method C. ESI-MS m / z 251 (M+H + )

[0776] 3) Synthesis of intermediate 4 (methyl 1-((1-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate): Synthesized using the above synthetic method A. ESI-MS m / z 740 (M+H + )

[0777] 4) Synthesis of intermediate 5 (methyl 1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate): The intermediate 4 (796 mg, 1.08 mmol) was dissolved in DCM (10.8 mL), and 1 M BCl3 (7.5 ml, 7.53 mmol) was added dropwise and stirred at room temperature for 30 minutes. The organic layer extracted with DCM and saturated aqueous NaHCO3 was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 5 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 560 (M+H + )

[0778] 5) H-113 (1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 546 (M+H + )

[0779] (42) Representative synthesis example 42

[0780] The synthetic route of the above H-114 is specified below.

[0781]

[0782] 1) Synthesis of intermediate 2 (methyl 1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate): The intermediate 1 (150 mg, 0.27 mmol) and 10% Pd / C (43 mg, 0.04 mmol) were dissolved in MeOH (2.7 mL) and stirred under hydrogen for 2 days. After completion of the reaction, the mixture was filtered through celite and washed with MeOH. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain intermediate 2. ESI-MS m / z 564 (M+H + )

[0783] 2) H-114 (1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-oxopiperidine-4-carboxylic acid) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 550 (M+H + )

[0784] [Synthesis Example 4] Specific synthesis of the conjugate

[0785] (1) Representative synthesis method 1

[0786] Compound 12 was synthesized using the synthetic route below.

[0787]

[0788] 1) Synthesis of Intermediate 2 (2,4-dihydroxy-5-isopropylbenzaldehyde): DMF (31 mL, 0.39 mol) was cooled, and POCl3 (37 mL, 0.39 mol) was slowly added while stirring. After 30 minutes, intermediate 1 (20 g, 0.13 mol) dissolved in DMF (40 mL) was slowly added to the cooling reaction mixture while stirring. After 30 minutes, the mixture was stirred at room temperature for 2 hours, heated to 50°C, and stirred for another 2 hours. After the reaction was complete, it was cooled, and the reaction mixture was slowly added to an aqueous solution of NaOH (65 g) dissolved in H2O (400 mL) while stirring. When the reaction mixture turned red, it was heated to 70°C, stirred for 30 minutes, and cooled to room temperature. HCl was slowly added while stirring until the pH reached 2-3, and when the reaction mixture turned yellow, the solid was filtered and washed with water. Intermediate 2 was obtained by drying at 50°C and used in the next reaction without purification. ESI-MSm / z153 (M+H + )

[0789] 2) Synthesis of intermediate 3 (2,4-bis(benzyloxy)-5-isopropylbenzaldehyde): The intermediate 2 (18 g, 0.10 mol) and K2CO3 (41 g, 0.30 mol) were added to acetone (400 mL), stirred, and benzyl bromide (27 mL, 0.23 mol) was added. The mixture was heated and stirred under reflux overnight. After the reaction was completed, the mixture was cooled and the solid was filtered off. The organic layer was concentrated under reduced pressure, and hexane was added and stirred overnight. The solid was filtered off and dried to obtain intermediate 3, which was used in the next reaction without purification. ESI-MS m / z 361 (M+H + )

[0790] 3) Synthesis of intermediate 4 (2,4-bis(benzyloxy)-5-isopropylbenzoic acid)

[0791] - Method A: The intermediate 3 (20 g, 55 mmol) was dissolved in ceric ammonium nitrate (220 mL), and CuCl (0.55 g, 5.5 mmol) and tert-butyl hydroperoxide (22 mL, 220 mmol) were added. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with a saturated aqueous solution of NaHSO3 and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 4, which was used in the next reaction without purification.

[0792] - Method B: The intermediate 3 (20 g, 55 mmol) and sulfamic acid (20 mL, 440 mmol) were dissolved in DMSO (13 mL) and THF (132 mL), cooled, and stirred. NaClO2 (40 g, 440 mmol) dissolved in H2O (132 mL) was added to the cooled reaction mixture, and stirred at room temperature for 4 hours. The organic layer extracted with EA was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 4. ESI-MS m / z 377 (M+H + )

[0793] 4) Synthesis of intermediate 5 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-bromoisoindolin-2-yl)methanone): The intermediate 4 (16 g, 43 mmol) and 5-bromoisoindoline (8.4 g, 43 mmol) were dissolved in DMF (142 mL), and EDCI HCl (8.9 g, 46.7 mmol), HOBt (7.2 g, 46.7 mmol), and iPr2EtN (22.2 mL, 127.5 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, extraction was performed using IPA / CHCl3 (1:3), H2O, and a saturated aqueous solution of NaCl. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 5 was obtained by purification by MPLC (EA / Hex). ESI-MSm / z556 (M+H+ )

[0794] 5) Synthesis of intermediate 6 (tert-butyl 4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate): The intermediate 5 (10 g, 18 mmol), potassium ((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)trifluoroborate (0.82 g, 27 mmol) and Cs2CO3 (17.6 g, 54 mmol) were dissolved in THF (160 mL) and H2O (16 mL), and the gas was removed by sonication for 5 min under nitrogen. Pd(OAc)2 (0.2 g, 9 mmol) and XPhos (0.085 g, 2 mmol) were added to the reaction mixture, and the mixture was stirred at 80°C for 24 h. After the reaction was completed, it was cooled to room temperature, filtered through Celite, and washed with EA. The obtained filtrate was concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 6. ESI-MS m / z 676 (M+H + )

[0795] 6) Synthesis of intermediate 7 ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-(piperazin-1-ylmethyl)isoindolin-2-yl)methanone): The intermediate 6 (9 g, 13.3 mmol) was dissolved in DCM (44.4 mL), 4M HCl (16.6 mL, 66.6 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain intermediate 7, which was used in the next reaction without purification. ESI-MS m / z 576 (M+H + )

[0796] 7) Synthesis of intermediate 8 (tert-butyl 4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate): The intermediate 7 (8.8 g, 15 mmol) was dissolved in DCE (51 mL), and 1-(tert-butoxycarbonyl)-4-piperidinecarboxaldehyde (6.5 g, 31 mmol) and NaBH(OAc)3 (3.6 mg, 17 mmol) were added. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, extraction was performed using DCM and a saturated aqueous solution of NaHCO3. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 8. ESI-MSm / z773 (M+H + )

[0797] 8) Synthesis of H-7-Bn ((2,4-bis(benzyloxy)-5-isopropylphenyl)(5-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)isoindolin-2-yl)methanone): The intermediate 8 (7 g, 9.1 mmol) was dissolved in DCM (30 mL), 4M HCl (11 mL, 45 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain H-7-Bn, which was used in the next reaction without purification. ESI-MS m / z 673 (M+H + )

[0798] 9) Synthesis of intermediate 10 (tert-butyl 2-chloro-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate): The intermediate 9 (30 g, 98.6 mmol) was dissolved in THF (329 mL), and morpholine (9.4 mL, 108.49 mmol) and TEA (15.1 mL, 108.49 mmol) were added, and the mixture was stirred at 40°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with EA and H2O. The organic layer was washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 10, which was used in the next reaction without purification. ESI-MS m / z 355 (M+H + )

[0799] 10) Synthesis of intermediate 11 (tert-butyl 2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate): The intermediate 10 (25 g, 70.5 mmol), 2-aminopyrimidine-5-boronic acid (10.8 g, 77.5 mmol), and Na2CO3 (22.4 g, 211 mmol) were dissolved in DMF (235 mL) and H2O (58 mL), and the gas was removed by ultrasonication for 5 min under nitrogen. Pd(PPh3)4 (4.07 g, 3.52 mmol) was added to the reaction mixture, and the mixture was stirred at 100°C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through Celite, and washed with EA. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (EA / Hex) to obtain intermediate 11. ESI-MSm / z414 (M+H + )

[0800] 11) Synthesis of P-2 (5-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)pyrimidin-2-amine): The intermediate 11 (15 g, 36.3 mmol) was dissolved in DCM (121 mL), 4 M HCl (45.3 mL, 181 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the residue was concentrated under reduced pressure to obtain P-2, which was used in the next reaction without purification. ESI-MS m / z 314 (M+H + )

[0801] 12) Synthesis of intermediate 12 (tert-butyl 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetate): The above P-2 (13 g, 41.5 mmol) was dissolved in CAN (138 mL), and tert-butyl bromoacetate (6.79 mL, 45.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted using EA and H2O, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 12, which was used in the next reaction without purification. ESI-MS m / z 428 (M+H + )

[0802] 13) P-1 (2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetic acid) Synthesis: The intermediate 12 (14 g, 32.7 mmol) was dissolved in DCM (109 mL), 4 M HCl (40.9 mL, 164 mmol) was added, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain P-1, which was used in the next reaction without purification. ESI-MS m / z 372 (M+H + )

[0803] 14) Synthesis of intermediate 13 (2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-bis(benzyloxy)-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethanone): After dissolving the above P-1 (100 mg, 0.27 mmol) and H-7-Bn (181 mg, 2.7 mmol) in DCE (1.3 mL), EDCI HCl (56.8 mg, 0.30 mmol), HOAt (40.3 mg, 0.30 mmol) and iPr2EtN (0.14 mL, 0.81 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the mixture was washed sequentially with DCM, 2 M HCl, and 2 M NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The intermediate 13 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 1026 (M+H + )

[0804] 15) Synthesis of compound 12 (2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethanone)

[0805] - Method A: The intermediate 13 (100 mg, 0.10 mmol) and 10% Pd / C (1.1 mg, 0.01 mmol) were dissolved in THF (1 mL) and MeOH (0.1 mL), and stirred overnight under hydrogen. After completion of the reaction, the mixture was filtered through Celite and washed with EA. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain compound 12.

[0806] - Method B: The intermediate 13 (100 mg, 0.10 mmol) and Pd(OH)2 (1.37 mg, 0.01 mmol) were dissolved in THF (1 mL) and MeOH (0.1 mL), and stirred overnight under hydrogen. After completion of the reaction, the mixture was filtered through Celite and washed with EA. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain compound 12.

[0807] - Method C: The intermediate 13 (100 mg, 0.10 mmol) and pentamethylbenzene (43.34 mg, 0.29 mmol) were dissolved in DCM (1 mL), cooled to -78°C, and stirred. BCl3 (1.0 MinDCM, 0.20 mL, 0.19 mmol) was slowly added, and stirred for 30 minutes. After completion of the reaction, the mixture was quenched with CHCl3-MeOH (10:1), heated to room temperature, concentrated under reduced pressure, and purified by MPLC (MeOH / DCM) to obtain compound 12.

[0808] - Method D: The intermediate 13 (100 mg, 0.10 mmol), NaHCO3 (24.6 mg, 0.30 mmol), and Pd(OH)2 (1.37 mg, 0.01 mmol) were dissolved in H2O (1 mL) and stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through celite and washed with EA. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (MeOH / DCM) to obtain compound 12.

[0809] - Method E: The intermediate 13 (100 mg, 0.10 mmol) was dissolved in TFA (1 mL), and trifluoromethanesulfonic acid (0.5 mL, 6 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with EA and a saturated aqueous solution of NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 12 was obtained by purification with MPLC (MeOH / DCM). ESI-MS m / z 846 (M+H + )

[0810] Compound 1: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one

[0811]

[0812] Compound 1 was synthesized using the above synthetic methods B and G using P-1 and H-1-Bn as starting materials. ESI-MSm / z749 (M+H + )

[0813] (2) Representative synthesis method 2

[0814] Compound 2 was synthesized using the synthetic route below.

[0815]

[0816] 1) Synthesis of Intermediate 2 (2,4-Dihydroxy-5-isopropylbenzodithioic acid): The intermediate 1 (20.00 g, 131.4 mmol) was dissolved in anhydrous DMF (78.88 mL), and CS2 (10.30 mL, 170.8 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours. After cooling the reaction mixture to room temperature, it was mixed with water, and the pH was adjusted to 1 to 2 using aqueous hydrochloric acid solution. The reaction mixture was filtered, and the precipitate was recrystallized from ethanol to obtain Intermediate 2. ESI-MS m / z 229 (M+H + )

[0817] 2) Synthesis of intermediate 3 (tert-butyl 4-(4-(2,4-dihydroxy-5-isopropylphenylthioamido)benzyl)piperazine-1-carboxylate): The intermediate 2 (29.00 g, 127.0 mmol), sodium chloroacetate (22.19 g, 190.5 mmol), and sodium bicarbonate (32.01 g, 381.0 mmol) were dissolved in DMF (158.8 mL) and stirred at 30°C for 3 hours. tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (37.01 g, 127.0 mmol) was added to the reaction mixture and stirred at 80°C for 4 hours. The reaction mixture was mixed with ice water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 3 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z486 (M+H + )

[0818] 3) Synthesis of intermediate 4 (tert-butyl 4-(4-(7-hydroxy-6-isopropyl-2-oxo-4-thioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzyl)piperazine-1-carboxylate): The intermediate 3 (34.00 g, 70.01 mmol) and CDI (22.70 g, 140.0 mmol) were dissolved in THF (140.0 mL) and stirred at room temperature for 4 hours. The reaction mixture was extracted with brine and EA. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate 4. ESI-MS m / z 512 (M+H + )

[0819] 4) Synthesis of intermediate 5 (tert-butyl 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carboxylate): Hydrazine monohydrate (5.812 g, 116.1 mmol) was added to a solution of intermediate 4 (33.00 g, 64.50 mmol) in ethanol (50.00 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to obtain intermediate 5. ESI-MS m / z 510 (M+H + )

[0820] 5) Synthesis of H-2 (5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(piperazin-1-ylmethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one): The intermediate 5 (11.00 g, 21.59 mmol) was dissolved in a 4.0 M HCl 1,4-dioxane solution (26.98 mL) and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain H-2. ESI-MS m / z 410 (M+H + )

[0821] 6) Synthesis of compound 2 (2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethan-1-one): H-2 (50.0 mg, 0.122 mmol), P-1 (45.3 mg, 0.122 mmol), EDCI HCl (35.1 mg, 0.183 mmol) were dissolved in pyridine (0.611 mL), and stirred at room temperature for 16 hours. The reaction mixture was extracted with IPA / CHCl3 (1:3) and aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 2 was obtained by purification with MPLC (MeOH / DCM). ESI-MS m / z 763 (M+H +)

[0822] Compound 3: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one

[0823]

[0824] Compound 3 was synthesized using synthetic methods B and G using P-2 and H-3 as starting materials. ESI-MS m / z 846 (M+H + )

[0825] Compound 4: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one

[0826]

[0827] Compound 4 was synthesized using synthetic methods B and G using P-2 and H-4 as starting materials. ESI-MS m / z 749 (M+H + )

[0828] Compound 5: (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0829]

[0830] Compound 5 was synthesized using synthetic methods B and G using P-3 and H-5-Bn as starting materials. ESI-MS m / z 817 (M+H + )

[0831] Compound 6: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butan-1-one

[0832]

[0833] Compound 6 was synthesized using synthetic methods B and G using P-2 and H-6 as starting materials. ESI-MS m / z 777 (M+H + )

[0834] Compound 7: (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0835]

[0836] Compound 7 was synthesized using synthetic methods B and G using P-2 and H-5-Bn as starting materials. ESI-MS m / z 734 (M+H + )

[0837] Compound 8: 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one

[0838]

[0839] Compound 8 was synthesized using synthetic methods B and G using P-4 and H-7-Bn as starting materials. ESI-MS m / z 913 (M+H + )

[0840] Compound 9: 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one

[0841]

[0842] Compound 9 was synthesized using synthetic method B using P-4 and H-8 as starting materials. ESI-MS m / z 899 (M+H + )

[0843] Compound 10: (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0844]

[0845] Compound 10 was synthesized using synthetic method B using P-2 and H-9 as starting materials. ESI-MS m / z 825 (M+H + )

[0846] Compound 11: (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0847]

[0848] Compound 11 was synthesized using synthetic methods B and G using P-5 and H-5-Bn as starting materials. ESI-MS m / z 845 (M+H + )

[0849] Compound 12: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one

[0850]

[0851] Compound 12 was synthesized using synthetic methods B and G using P-1 and H-7-Bn as starting materials. ESI-MS m / z 846 (M+H + )

[0852] Compound 13: (4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0853]

[0854] Compound 13 was synthesized using synthetic methods B and G using P-6 and H-5-Bn as starting materials. ESI-MS m / z 912 (M+H + )

[0855] Compound 14: (4-(2-(2-Aminobenzo[d]oxazol-6-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0856]

[0857] Compound 14 was synthesized using synthetic methods B and G using P-7 and H-5-Bn as starting materials. ESI-MS m / z 884 (M+H + )

[0858] Compound 15: (4-(2-(1H-indazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0859]

[0860] Compound 15 was synthesized using synthetic methods B and G using P-8 and H-5-Bn as starting materials. ESI-MS m / z 868 (M+H + )

[0861] Compound 16: (5-((4-(4-(2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0862]

[0863] Compound 16 was synthesized using synthetic method B using P-9 and H-9 as starting materials. ESI-MS m / z 864 (M+H + )

[0864] Compound 17: (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0865]

[0866] Compound 17 was synthesized using synthetic method B using P-10 and H-9 as starting materials. ESI-MS m / z 892 (M+H + )

[0867] Compound 18: (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)phenyl)methanone

[0868]

[0869] Compound 18 was synthesized using synthetic method B using P-2 and H-12 as starting materials. ESI-MS m / z 839 (M+H + )

[0870] Compound 19: (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0871]

[0872] Compound 19 was synthesized using synthetic methods B and G using P-2 and H-13 as starting materials. ESI-MS m / z 826 (M+H + )

[0873] Compound 20: (5-((4-(2-(2-Aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0874]

[0875] Compound 20 was synthesized using synthetic method B using P-9 and H-5 as starting materials. ESI-MS m / z 773 (M+H + )

[0876] Compound 21: (5-((5-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0877]

[0878] Compound 21 was synthesized using synthetic methods B and G using P-2 and H-14 as starting materials. ESI-MS m / z 851 (M+H + )

[0879] Compound 22: (5-((4-((6-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-3-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0880]

[0881] Compound 22 was synthesized using synthetic methods B and G using P-2 and H-15 as starting materials. ESI-MS m / z 826 (M+H + )

[0882] Compound 23: (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone

[0883]

[0884] Compound 23 was synthesized using synthetic methods B and G using P-2 and H-16 as starting materials. ESI-MS m / z 817 (M+H + )

[0885] Compound 24: (5-((4-(4-(2-(1H-indazol-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0886]

[0887] Compound 24 was synthesized using synthetic method B using P-12 and H-9 as starting materials. ESI-MS m / z 848 (M+H + )

[0888] Compound 25: (S)-(5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0889]

[0890] Compound 25 was synthesized using synthetic methods A and G using P-18 and H-68 as starting materials. ESI-MS m / z 720 (M+H + )

[0891] Compound 26: ((S)-3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)((S)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)pyrrolidin-3-yl)methanone

[0892]

[0893] Compound 26 was synthesized using synthetic methods B and G using P-18 and H-18 as starting materials. ESI-MS m / z 817 (M+H + )

[0894] Compound 27: (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone

[0895]

[0896] Compound 27 was synthesized using synthetic methods B and G using P-18 and H-19 as starting materials. ESI-MS m / z 803 (M+H + )

[0897] Compound 28: (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0898]

[0899] Compound 28 was synthesized using synthetic methods B and G using P-2 and H-20 as starting materials. ESI-MS m / z 825 (M+H + )

[0900] Compound 29: (5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0901]

[0902] Compound 29 was synthesized using synthetic methods A and G using P-13 and H-68 as starting materials. ESI-MS m / z 706 (M+H + )

[0903] Compound 30: (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0904]

[0905] Compound 30 was synthesized using synthetic method B using P-18 and H-5 as starting materials. ESI-MS m / z 831 (M+H + )

[0906] Compound 31: (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0907]

[0908] Compound 31 was synthesized using synthetic method B using P-2 and H-22 as starting materials. ESI-MS m / z 811 (M+H + )

[0909] (3) Representative synthesis method 3

[0910] Compound 32 was synthesized using the synthetic route below.

[0911]

[0912] 1) Synthesis of intermediate 2 (N-(2,4-dichloro-5-hydroxyphenyl)acetamide): SO2Cl2 (36.60 g, 271.2 mmol) was slowly added dropwise to a solution of intermediate 1 (20.00 g, 132.3 mmol) in acetic acid (132.3 mL) at 37°C, and the mixture was stirred for 1 hour. After cooling the reaction mixture to 8°C, water was added, and the mixture was stirred for 1 hour. The reaction mixture was filtered, and the filtered solution was concentrated under reduced pressure to obtain intermediate 2. ESI-MS m / z 220 (M+H + )

[0913] 2) Synthesis of intermediate 3 (N-(5-(benzyloxy)-2,4-dichlorophenyl)acetamide): The intermediate 2 (28.00 g, 127.2 mmol), BnBr (28.29 g, 165.4 mmol), and K2CO3 (35.17 g, 254.5 mmol) were dissolved in DMF (127.2 mL) and stirred at 25°C for 16 hours. After completion of the reaction, the mixture was extracted with DCM and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 3 was obtained by purification by MPLC (EA / Hex). ESI-MS m / z 310 (M+H + )

[0914] 3) Synthesis of intermediate 4 (5-(benzyloxy)-2,4-dichloroaniline): The intermediate 3 (24.00 g, 77.38 mmol) was dissolved in a mixture of ethanol (77.38 mL) and 35% aqueous hydrochloric acid solution (77.38 mL), and stirred at 60°C for 24 hours. The reaction mixture was cooled to room temperature and extracted with CHCl3 and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The intermediate 4 was obtained by purification with MPLC (MeOH / DCM). ESI-MS m / z 268 (M+H + )

[0915] 4) Synthesis of intermediate 5 (1-(benzyloxy)-2,4-dichloro-5-iodobenzene): The intermediate 4 (16.00 g, 59.67 mmol) was dissolved in acetic acid (198.9 mL), 1.0 M HCl (59.67 mL) was added, and the mixture was cooled to below 5°C. A solution of NaNO2 (4.734 g, 68.62 mmol) in water (34.31 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was added to a solution of KI (19.81 g, 119.3 mmol) and I2 (3.786 g, 14.92 mmol) in water (198.9 mL), and the mixture was stirred for 90 minutes. The reaction mixture was extracted using DCM, an aqueous sodium thiosulfate solution, an aqueous sodium hydroxide solution, water, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The mixture was purified by MPLC (EA / Hex) to obtain intermediate 5. ESI-MS m / z 379 (M+H + )

[0916] 5) Synthesis of intermediate 6 (2-(5-(benzyloxy)-2,4-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane): A solution of intermediate 5 (17.00 g, 44.85 mmol), K2CO3 (13.21 g, 134.6 mmol), and B2pin2 (13.67 g, 53.82 mmol) dissolved in DMF (149.5 mL) was degassed under nitrogen atmosphere. Pd(OAc)2 (503.5 mg, 2.243 mmol) was added to the reaction mixture and stirred at 80°C for 1 hour. The reaction mixture was filtered, and the filtered solution was concentrated under reduced pressure to obtain intermediate 6. ESI-MS m / z 379 (M+H + )

[0917] 6) Synthesis of intermediate 7 (2-amino-4-(5-(benzyloxy)-2,4-dichlorophenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide): A solution of intermediate 6 (16.00 g, 42.21 mmol), ethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (11.42 g, 44.32 mmol), and K3PO4 (17.92 g, 84.41 mmol) dissolved in a mixture of 1,4-dioxane (112.6 mL) and water (28.14 mL) was degassed under a nitrogen atmosphere. Pd(PPh3)4 (2.439 g, 2.110 mmol) was added to the reaction mixture and stirred at 110°C for 4 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was extracted with DCM and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The intermediate 7 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 473 (M+H + )

[0918] 7) Synthesis of intermediate 8 (2-amino-4-(2,4-dichloro-5-hydroxyphenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide): A solution of intermediate 7 (13.00 g, 27.46 mmol) and pentamethylbenzene (12.21 g, 82.39 mmol) dissolved in 137.3 mL of DCM was cooled to -78°C, and 1.0 M BCl3DCM solution (54.93 mL, 54.93 mmol) was slowly added dropwise to the reaction mixture and stirred for 15 minutes. A mixture of MeOH and CHCl3 was added to the reaction mixture, and the mixture was warmed to room temperature and concentrated under reduced pressure. Intermediate 8 was obtained by purification by MPLC (MeOH / DCM). ESI-MS m / z 383 (M+H + )

[0919] 8) Synthesis of intermediate 9 (tert-butyl 4-(2-(5-(2-amino-6-(ethylcarbamoyl)thieno[2,3-d]pyrimidin-4-yl)-2,4-dichlorophenoxy)ethyl)piperazine-1-carboxylate): The intermediate 8 (8.00 g, 20.9 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (4.81 g, 20.9 mmol), and triphenylphosphine (6.57 g, 25.0 mmol) were dissolved in THF (104 mL), and then cooled to 0°C. DIAD (4.87 mL, 25.0 ml) was slowly added dropwise to the reaction mixture, and stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Intermediate 9 was obtained by purification by MPLC (MeOH / DCM). ESI-MSm / z595 (M+H + )

[0920] 9) Synthesis of H-23 (2-amino-4-(2,4-dichloro-5-(2-(piperazin-1-yl)ethoxy)phenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide): The intermediate 9 (7.00 g, 11.8 mmol) was dissolved in a 4.0 M HCl 1,4-dioxane solution (14.7 mL) and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain H-23. ESI-MS m / z 495 (M+H + )

[0921] 10) Synthesis of compound 32 (2-amino-4-(5-(2-(4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperazin-1-yl)ethoxy)-2,4-dichlorophenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide): H-23 (50.0 mg, 0.101 mmol), P-1 (37.5 mg, 0.101 mmol), EDCI HCl (29.0 mg, 0.151 mmol) were dissolved in pyridine (0.505 mL), and stirred at room temperature for 16 hours. The reaction mixture was extracted with IPA / CHCl3 (1:3) and aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound 35 was obtained by purification with MPLC (MeOH / DCM). ESI-MS m / z 848 (M+H + )

[0922] Compound 33: (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)methanone

[0923]

[0924] Compound 33 was synthesized using synthetic method B using P-3 and H-24 as starting materials. ESI-MS m / z 928 (M+H + )

[0925] Compound 34: (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0926]

[0927] Compound 34 was synthesized using synthetic method B using P-14 and H-9 as starting materials. ESI-MS m / z 825 (M+H + )

[0928] Compound 35: (4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone

[0929]

[0930] Compound 35 was synthesized using synthetic method B using P-14 and H-24 as starting materials. ESI-MS m / z 845 (M+H + )

[0931] Compound 36: (5-((4-((1r,4r)-4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0932]

[0933] Compound 36 was synthesized using synthetic method B using P-10 and H-25 as starting materials. ESI-MS m / z 912 (M+H + )

[0934] Compound 37: (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)sulfonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0935]

[0936] Compound 37 was synthesized using synthetic methods A and G using P-15 and H-68 as starting materials. ESI-MS m / z 881 (M+H + )

[0937] (4) Representative synthesis method 4

[0938] Compound 38 was synthesized using the synthetic route below.

[0939]

[0940] 1) Synthesis of intermediate 2 (N'-(3,3-dimethyl-5-oxocyclohexyridine)-4-methylbenzenesulfonohydrazide): The intermediate 1 (2 g, 14.27 mmol) was dissolved in toluene (90 mL), and then p-toluenesulfonylhydrazide (2.66 g, 14.27 mmol) and TsOH (0.25 g, 1.43 mmol) were added. The mixture was heated to 120°C and stirred for 2 hours. After completion of the reaction, the mixture was filtered at room temperature and washed with ether to obtain intermediate 2. ESI-MS m / z 309 (M+H + )

[0941] 2) Synthesis of intermediate 3 (6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one): The intermediate 2 (1.8 g, 5.85 mmol) was dissolved in THF (50 mL), and TEA (2.45 mL, 17.6 mmol) and TFAA (1.25 mL, 8.79 mmol) were added at room temperature, and the mixture was stirred at 55°C for 3 hours. After the reaction, MeOH and 1N NaOH (1:1_30 mL) were added, and the mixture was stirred for 3 hours. After completion of the reaction, the mixture was diluted with a saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated chloride water, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and purified by MPLC (EA / Hex) to obtain intermediate 3. ESI-MS m / z 233 (M+H + )

[0942] 3) Synthesis of intermediate 4 (tert-butyl 4-((2-cyano-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)piperidine-1-carboxylate): The intermediate 3 (350 mg, 1.51 mmol) was dissolved in 1,4-dioxane (5 mL), and K2CO3 (521 mg, 3.77 mmol) and H-26-A (688 mg, 1.81 mmol) were added at room temperature. Dimethylethylenediamine, DMEDA (66 mg, 0.75 mmol) and CuI (57 mg, 0.3 mmol) were added, and the mixture was stirred at 90°C for 12 hours. After completion of the reaction, the mixture was extracted with EA at room temperature, washed with saturated aqueous chloride, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by MPLC (EA / Hex) to obtain intermediate 4. ESI-MS m / z 532 (M+H + )

[0943] 4) H-26-A synthesis: The intermediate A-1 (750 mg, 3.75 mmol) was dissolved in DMSO (20 mL), and DIPEA (0.8 mL, 4.55 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (826 mg, 4.12 mmol) were added at room temperature, and the mixture was stirred at 100°C overnight. After completion of the reaction, the mixture was diluted with distilled water at room temperature, extracted with EA, washed with saturated aqueous chloride, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by MPLC (EA / Hex) to obtain intermediate H-26-A. ESI-MS m / z 380 (M+H + )

[0944] 5) Synthesis of intermediate 5 (tert-butyl 4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)piperidine-1-carboxylate): The intermediate 4 (250 mg, 0.47 mmol) was dissolved in EtOH / DMSO (4:1_4 mL, 1 mL), and 1N NaOH (0.2 mL, 0.19 mmol) was added at 10°C, followed by stirring for 10 minutes. After the reaction, H2O2 (30 wt%_0.2 mL, 0.19 mmol) was added, and the mixture was stirred for 2 hours. After completion of the reaction, the mixture was extracted with EA at room temperature, washed with saturated aqueous chloride, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and purified by MPLC (EA / Hex) to obtain intermediate 5. ESI-MSm / z550 (M+H + )

[0945] 6) H-26 (4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)-2-(piperidin-4-yl-amino)benzamide) Synthesis: Synthesized using the above synthetic method C. ESI-MS m / z 450 (M+H + )

[0946] 7) Synthesis of compound 38 (2-((1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperidin-4-yl)amino)-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide): Synthesized using the above synthetic method B. ESI-MS m / z 803 (M+H + )

[0947] Compound 39: (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0948]

[0949] Compound 39 was synthesized using synthetic method B using P-2 and H-27 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.61 (s, 1H), 9.01 (d, J = 23.3 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.33 - 7.16 (m, 3H), 7.12 (s, 2H), 7.06 (d, J = 7.0 Hz, 4H), 6.39 (s, 1H), 4.72 (d, J = 25.4 Hz, 6H), 3.81 (s, 3H), 3.71 (d, J = 5.1 Hz, 5H), 3.53 - 3.44 (m, 9H), 3.17 - 3.01 (m, 1H), 2.74 (s, 2H), 2.42 (s, 6H), 1.13 (d, J = 6.9 Hz, 7H). ESI-MSm / z855 (M+H + )

[0950] Compound 40: (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0951]

[0952] Compound 40 was synthesized using synthetic method B using P-10 and H-27 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.61 (s, 1H), 8.56 - 8.38 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.33 - 7.16 (m, 3H), 7.06 (d, J = 7.2 Hz, 3H), 6.82 (s, 3H), 6.39 (s, 1H), 4.76 (s, 4H), 4.70 - 4.48 (m, 2H), 3.80 (s, 3H), 3.72 - 3.64 (m, 4H), 3.56 - 3.39 (m, 10H), 3.15 - 3.03 (m, 1H), 2.81 - 2.71 (m, 2H), 2.42 (s, 8H), 1.13 (d, J = 6.9 Hz, 6H). ESI-MSm / z922 (M+H + )

[0953] Compound 41: (5-(((R)-4-(((1r,4R)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0954]

[0955] Compound 41 was synthesized using synthetic method B using P-2 and H-28 as starting materials. ESI-MS m / z 861 (M+H + )

[0956] Compound 42: 2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)propan-1-one

[0957]

[0958] Compound 42 was synthesized using synthetic method B using P-16 and H-1 as starting materials. ESI-MS m / z 846 (M+H + )

[0959] Compound 43: (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-fluorobenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0960]

[0961] Compound 43 was synthesized using synthetic method B using P-2 and H-29 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.62 (s, 1H), 9.02 (d, J = 23.9 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.38 - 7.18 (m, 5H), 7.13 (s, 2H), 7.05 (s, 1H), 6.40 (s, 1H), 4.72 (d, J = 26.1 Hz, 6H), 3.71 (d, J = 5.0 Hz, 4H), 3.60 - 3.45 (m, 10H), 3.15 - 3.04 (m, 1H), 2.79 - 2.72 (m, 2H), 2.43 (s, 8H), 1.14 (d, J = 6.9 Hz, 6H). ESI-MSm / z843 (M+H + )

[0962] Compound 44: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)propan-1-one

[0963]

[0964] Compound 44 was synthesized using synthetic method B using P-17 and H-7 as starting materials. ESI-MS m / z 860 (M+H + )

[0965] Compound 45: (S)-(5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0966]

[0967] Compound 45 was synthesized using synthetic method A using P-77 and H-45 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.60 (s, 1H), 9.05 (s, 2H), 7.43 (q, J = 8.0 Hz, 4H), 7.21 (s, 3H), 7.08 (d, J = 21.8 Hz, 3H), 6.39 (s, 1H), 4.64 (d, J = 69.8 Hz, 7H), 4.09 (d, J = 14.2 Hz, 1H), 3.71 (s, 6H), 3.47 (d, J = 16.0 Hz, 9H), 3.15 - 3.03 (m, 1H), 2.74 (s, 3H), 2.61 (s, 1H), 2.44 (s, 1H), 2.12 (d, J = 29.2 Hz, 3H), 1.13 (d, J = 6.9 Hz, 6H). ESI-MSm / z855 (M+H + )

[0968] Compound 46: (5-((9-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0969]

[0970] Compound 46 was synthesized using synthetic method A using P-77 and H-33 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.61 (s, 1H), 9.05 (s, 2H), 7.52 - 7.34 (m, 4H), 7.16 (dd, J = 47.9, 21.9 Hz, 6H), 6.39 (s, 1H), 4.83 (d, J = 45.7 Hz, 7H), 3.76 (d, J = 25.4 Hz, 5H), 3.55 - 3.44 (m, 8H), 3.09 (p, J = 6.9 Hz, 1H), 2.75 (s, 2H), 2.34 (s, 6H), 1.42 (s, 8H), 1.24 - 1.09 (m, 8H). ESI-MSm / z893 (M+H + )

[0971] Compound 47: (5-((4-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0972]

[0973] Compound 47 was synthesized using synthetic method A using P-77 and H-7 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.61 (s, 1H), 9.05 (s, 2H), 7.51 - 7.35 (m, 4H), 7.16 (d, J = 25.1 Hz, 5H), 7.04 (s, 1H), 6.40 (s, 1H), 4.76 (s, 6H), 3.82 - 3.41 (m, 14H), 3.15 - 3.02 (m, 1H), 2.75 (s, 4H), 2.22 (d, J = 73.4 Hz, 12H), 1.64 (s, 2H), 1.46 (s, 1H), 1.13 (d, J = 6.9 Hz, 8H). ESI-MSm / z922 (M+H + )

[0974] Compound 48: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)propan-1-one

[0975]

[0976] Compound 48 was synthesized using synthetic method B using P-17 and H-33 as starting materials. ESI-MS m / z 831 (M+H + )

[0977] Compound 49: (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0978]

[0979] Compound 49 was synthesized using synthetic method B using P-2 and H-34 as starting materials. ESI-MS m / z 827 (M+H + )

[0980] Compound 50: (S)-(5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0981]

[0982] Compound 50 was synthesized using synthetic method B using P-2 and H-35 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.08 (d, J = 26.2 Hz, 2H), 8.93 - 8.80 (m, 2H), 7.48 (s, 5H), 7.02 (s, 1H), 6.43 (s, 1H), 4.78 (d, J = 14.6 Hz, 6H), 4.38 (d, J = 34.6 Hz, 5H), 3.59 (s, 6H), 3.14 (s, 14H), 2.80 (s, 2H), 1.13 (d, J = 6.9 Hz, 6H). ESI-MSm / z857 (M+H + )

[0983] Compound 51: (5-((4-(2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)-2-hydroxyethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0984]

[0985] Compound 51 was synthesized using synthetic method B using P-2 and H-65 as starting materials. ESI-MS m / z 855 (M+H + )

[0986] Compound 52: (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0987]

[0988] Compound 52 was synthesized using synthetic method B using P-2 and H-36 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.62 (s, 1H), 9.05 (d, J = 7.2 Hz, 2H), 8.63 (s, 1H), 7.35 - 7.16 (m, 4H), 7.13 (s, 2H), 7.05 (s, 1H), 6.40 (s, 1H), 5.24 (s, 1H), 4.74 (d, J = 14.4 Hz, 6H), 4.35 (d, J = 7.0 Hz, 2H), 4.24 (s, 1H), 3.83 (s, 1H), 3.72 (d, J = 5.0 Hz, 4H), 3.49 (s, 6H), 3.15 - 3.04 (m, 1H), 2.88 - 2.71 (m, 5H), 2.01 - 1.81 (m, 4H), 1.52 - 1.43 (m, 2H), 1.36 - 1.17 (m, 4H). ESI-MSm / z815 (M+H + )

[0989] Compound 53: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)ethan-1-one

[0990]

[0991] Compound 53 was synthesized using synthetic method B using P-1 and H-37 as starting materials.1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.59 (s, 1H), 9.00 (s, 2H), 7.20 (s, 1H), 7.05 (d, J = 16.3 Hz, 3H), 6.93 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 4.68 (s, 4H), 4.35 (d, J = 14.4 Hz, 2H), 4.01 (d, J = 13.1 Hz, 1H), 3.67 (d, J = 26.7 Hz, 6H), 3.46 (s, 4H), 3.36 (d, J = 7.7 Hz, 2H), 3.10 (q, J = 7.0 Hz, 1H), 2.96 (d, J = 12.6 Hz, 1H), 2.67 (s, 6H), 2.12 (d, J = 7.1 Hz, 4H), 1.89 (s, 2H), 1.71 (d, J = 12.1 Hz, 3H), 1.57 (d, J = 9.8 Hz, 2H), 1.13 (d, J = 6.9 Hz, 6H), 0.92 (d, J = 9.5 Hz, 3H). ESI-MSm / z847 (M+H + )

[0992] Compound 54: (R)-2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one

[0993]

[0994] Compound 54 was synthesized using synthetic method B using P-1 and H-38 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.60 (s, 1H), 9.00 (s, 2H), 7.32 - 7.17 (m, 3H), 7.08 (s, 2H), 7.03 (s, 1H), 6.39 (s, 1H), 4.75 (s, 4H), 4.26 - 4.05 (m, 2H), 3.71 (d, J = 5.1 Hz, 5H), 3.63 (s, 2H), 3.45 (t, J = 6.5 Hz, 7H), 3.14 - 3.04 (m, 1H), 2.86 - 2.59 (m, 8H), 2.10 - 1.77 (m, 4H), 1.13 (d, J = 6.9 Hz, 6H). ESI-MSm / z779 (M+H + )

[0995] Compound 55: 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one

[0996]

[0997] Compound 55 was synthesized using synthetic method B using P-1 and H-33 as starting materials. ESI-MS m / z 817 (M+H + )

[0998] Compound 56: (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[0999]

[1000] Compound 56 was synthesized using synthetic method B using P-19 and H-5 as starting materials. ESI-MS m / z 873 (M+H + )

[1001] Compound 57: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1002]

[1003] Compound 57 was synthesized using synthetic method B using P-20 and H-5 as starting materials. ESI-MS m / z 875 (M+H + )

[1004] Compound 58: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1005]

[1006] Compound 58 was synthesized using synthetic method B using P-2 and H-39 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.44 (dd, J = 4.3, 1.4 Hz, 1H), 8.26 (dd, J = 8.4, 1.5 Hz, 1H), 7.27 (dd, J = 8.4, 4.3 Hz, 4H), 7.13 (s, 2H), 7.04 (s, 1H), 6.45 (s, 1H), 4.73 (d, J = 11.8 Hz, 4H), 4.56 (s, 1H), 3.80 - 3.66 (m, 8H), 3.57 (p, J = 6.6 Hz, 4H), 3.18 - 3.02 (m, 4H), 2.77 - 2.70 (m, 2H), 2.68 - 2.58 (m, 2H), 1.81 - 1.67 (m, 2H), 1.25 - 1.22 (m, 4H), 1.14 (d, J = 6.9 Hz, 6H). ESI-MSm / z764 (M+H + )

[1007] Compound 59: 1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1008]

[1009] Compound 59 was synthesized using synthetic method B using P-19 and H-39 as starting materials. ESI-MS m / z 903 (M+H + )

[1010] Compound 60: (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1011]

[1012] Compound 60 was synthesized using synthetic method B using P-2 and H-40 as starting materials. ESI-MS m / z 750 (M+H + )

[1013] Compound 61: (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone

[1014]

[1015] Compound 61 was synthesized using synthetic method B using P-3 and H-40 as starting materials. ESI-MS m / z 833 (M+H + )

[1016] Compound 62: (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1017]

[1018] Compound 62 was synthesized using synthetic method B using P-19 and H-40 as starting materials. ESI-MS m / z 889 (M+H + )

[1019] Compound 63: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1020]

[1021] Compound 63 was synthesized using synthetic method B using P-20 and H-40 as starting materials. ESI-MS m / z 891 (M+H + )

[1022] Compound 64: (S)-(5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholine-4-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1023]

[1024] Compound 64 was synthesized using synthetic method B using P-21 and H-5 as starting materials. ESI-MS m / z 847 (M+H + )

[1025] Compound 65: 1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1026]

[1027] Compound 65 was synthesized using synthetic method B using P-3 and H-39 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.62 (s, 1H), 9.04 (s, 2H), 7.37 - 7.20 (m, 4H), 7.13 (s, 2H), 7.05 (s, 1H), 6.41 (d, J = 1.3 Hz, 1H), 4.77 (s, 4H), 4.69 (s, 1H), 4.60 (d, J = 16.4 Hz, 1H), 4.33 (d, J = 12.0 Hz, 1H), 3.86 (d, J = 11.5 Hz, 2H), 3.72 (s, 5H), 3.50 (d, J = 12.4 Hz, 7H), 3.10 (p, J = 6.9 Hz, 2H), 2.85 (s, 2H), 2.64 (s, 2H), 2.03 (s, 1H), 1.96 (d, J = 10.4 Hz, 2H), 1.75 (s, 1H), 1.62 (s, 3H), 1.24 (s, 4H), 1.19 (d, J = 6.2 Hz, 2H), 1.14 (d, J = 7.0 Hz, 6H). ESI-MSm / z847 (M+H + )

[1028] Compound 66: (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone

[1029]

[1030] Compound 66 was synthesized using synthetic method B using P-22 and H-1 as starting materials. ESI-MS m / z 813 (M+H + )

[1031] Compound 67: (S)-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone

[1032]

[1033] Compound 67 was synthesized using synthetic method B using P-22 and H-45 as starting materials. ESI-MS m / z 843 (M+H + )

[1034] Compound 68: (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone

[1035]

[1036] Compound 68 was synthesized using synthetic method B using P-22 and H-41 as starting materials. 1 H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 9.13 (s, 2H), 8.46 - 8.35 (m, 2H), 7.54 (s, 1H), 7.20 (s, 2H), 7.02 (s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.83 (s, 2H), 4.70 (s, 6H), 3.92 (s, 9H), 3.26 - 3.00 (m, 5H), 2.84 (s, 2H), 1.98 (s, 2H), 1.64 (s, 2H), 1.13 (d, J = 6.9 Hz, 6H). ESI-MSm / z814 (M+H + )

[1037] Compound 69: (5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1038]

[1039] Compound 69 was synthesized using synthetic method B using P-23 and H-5 as starting materials. ESI-MS m / z 883 (M+H + )

[1040] Compound 70: 1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1041]

[1042] Compound 70 was synthesized using synthetic method B using P-23 and H-39 as starting materials. ESI-MS m / z 913 (M+H + )

[1043] Compound 71: (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1044]

[1045] Compound 71 was synthesized using synthetic method B using P-2 and H-42 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.60 (s, 1H), 9.03 (s, 2H), 8.24 (s, 1H), 7.82 (s, 1H), 7.25 (s, 3H), 7.08 (d, J = 20.4 Hz, 3H), 6.39 (s, 1H), 4.77 (s, 6H), 4.22 (s, 1H), 3.73 (s, 6H), 3.51 (s, 6H), 3.14 - 3.03 (m, 1H), 2.95 - 2.85 (m, 2H), 2.84 - 2.68 (m, 2H), 2.10 (s, 2H), 1.99 (s, 4H), 1.14 (d, J = 6.9 Hz, 6H). ESI-MSm / z800 (M+H + )

[1046] Compound 72: (5-((1-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1047]

[1048] Compound 72 was synthesized using synthetic method A using P-77 and H-37 as starting materials. ESI-MS m / z 923 (M+H + )

[1049] Compound 73: (S)-(5-((4-((1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclopropyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone

[1050]

[1051] Compound 73 was synthesized using synthetic method A using P-78 and H-45 as starting materials. 1H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.12 (s, 2H), 7.48 (s, 5H), 7.02 (s, 1H), 6.44 (s, 1H), 4.79 (s, 6H), 3.69 (d, J = 23.0 Hz, 20H), 3.25 - 3.01 (m, 4H), 2.80 (s, 2H), 1.13 (d, J = 6.9 Hz, 10H). ESI-MSm / z819 (M+H + )

[1052] Compound 74: 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one

[1053]

[1054] Compound 74 was synthesized using synthetic method A using P-20 and H-62 as starting materials. ESI-MS m / z 861 (M+H + )

[1055] Compound 75: (S)-(5-((4-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)methyl)i...

Claims

1. A compound selected from a protein degrader or conjugate comprising a PI3K target moiety and an HSP90 target moiety connected via a linker, represented by the following chemical formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof: [Chemical Formula 1] XLY In the above chemical formula 1, X is a PI3K target moiety, L is a linker, and Y is an HSP90 target moiety.

2. In claim 1, A compound characterized in that in the above chemical formula 1, X has a structure of any one of the following chemical formulas 2 to 7: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] In the above chemical formula 2, is a single bond or a double bond, m1 and m2 can be equal or different and are 0 or 1, A1 to A5 may be the same or different and are any one of C, CH, CF, CH2, N and NH, R 1 is any one of hydrogen, morpholino and amino substituted pyrimidyl, R 2 is any one of halogen, unsubstituted or substituted aryl having 4 to 10 carbon atoms and substituted heteroaryl having 5 to 10 atoms containing at least one heteroatom selected from the group consisting of N, O and S, wherein the substituted aryl and heteroaryl are substituted with at least one selected from the group consisting of (C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Boc, trifluoromethyl and halogen, R 3 and R 4 may be the same or different, and are hydrogen or halogen, or R 3 and R 4 are linked to each other to form a 4 to 6 membered heteroaryl containing one or more heteroatoms selected from N or S, In the above chemical formula 3, R 5 and R 6 may be the same or different, and are hydrogen, (C1-C5)alkyl, or R 5 and R 6 are linked to each other to form aryls of 4 to 6 atoms, In the above chemical formula 4, R 7 Inland R 10 may be the same or different, and are hydrogen, halogen or trifluoromethyl, In the above chemical formula 5, R 11 Inland R 14 may be the same or different, and are hydrogen, (C1-C5)alkyl, halogen or trifluoromethyl, In the above chemical formula 6, R 15 Inland R 17 may be the same or different, and are hydrogen, (C1-C5)alkyl, halogen, amino, or (C1-C5)alkylsulfonamino, In the above chemical formula 7, R 18 is selected from hydrogen or (C1-C5)alkyl.

3. In claim 2, A compound characterized in that the chemical formula 2 is one of the chemical formulas 2-1 to 2-10 below, and the chemical formula 3 is the chemical formula 3-1 or 3-2 below: [Chemical Formula 2-1] [Chemical Formula 2-2] [Chemical Formula 2-3] [Chemical Formula 2-4] [Chemical Formula 2-5] [Chemical Formula 2-6] [Chemical Formula 2-7] [Chemical Formula 2-8] [Chemical Formula 2-9] [Chemical Formula 2-10] [Chemical Formula 3-1] [Chemical Formula 3-2] 4. In claim 2, The above R 2 is any one selected from the group consisting of halogen, morpholino, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidyl, unsubstituted or substituted benzoxazolyl, unsubstituted or substituted indazolyl, and unsubstituted or substituted phenyl, The above substituted pyridinyl, pyrimidyl, benzoxazolyl, indazolyl and phenyl are substituted with at least one selected from the group consisting of (C1-C3)alkyl, (C1-C3)alkoxy, amino, -NH-Boc, trifluoromethyl and halogen, The above R 7 Inland R 10 may be the same or different, and are fluorine, chlorine or trifluoromethyl, The above R 11 Inland R 14 may be the same or different, and are (C1-C2)alkyl, fluorine or trifluoromethyl, The above R 15 Inland R 17 may be the same or different, and are (C1-C2)alkyl, chlorine, amino, or (C1-C2)alkylsulfonamino, The above R 18 A compound characterized in that it is (C1-C3) alkyl.

5. In claim 1, A compound characterized in that in the above chemical formula 1, Y has a structure of any one of the following chemical formulas 8 to 12: [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] In the above chemical formula 8, B1 to B5 may be the same or different and are C, CH, CH2 or N, R 19 is hydrogen or amino, R 20 is hydrogen or oxygen, and R 20 When this is oxygen is a double bond, R 21 Inland R 24 may be the same or different, and is any one of hydrogen, hydroxy, benzyloxy, (C1-C5)alkyl or (C1-C5)alkoxy; R 21 and R 22 , R 22 and R 23 , or R 23 and R 24 are linked to each other to form a 4 to 6 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O, In the above chemical formula 9, R 25 Inland R 28 may be the same or different, and are hydrogen, hydroxy or (C1-C5)alkyl, In the above chemical formula 10, R 29 Inland R 32 may be the same or different, and are hydrogen, halogen, amino, or (C1-C5)alkyl, In the above chemical formula 11, R 33 Inland R 35 may be the same or different, and are hydrogen, (C1-C5)alkyl, halogen or trifluoromethyl, R 36 and R 37 may be the same or different, and are hydrogen or (C1-C5)alkyl, or R 36 and R 37 These are interconnected to form a six-ring ring, R 38 is hydrogen or (C1-C5)alkyl, m3 is 0 or 1, In the above chemical formula 12, R 39 Inland R 42 may be the same or different, and are selected from hydrogen, halogen, amino, (C1-C5)alkyl or (C1-C5)alkoxy.

6. In claim 5, The above chemical formula 8 is a compound characterized by being the following chemical formula 8-1 or 8-2: [Chemical Formula 8-1] [Chemical Formula 8-2] The above R 21 Inland R 24 may be the same or different, and are any one of hydrogen, halogen, hydroxy, benzyloxy, (C1-C3)alkyl or (C1-C3)alkoxy; R 21 and R 22 or R 22 and R 23 are linked to each other to form a 5-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N or O.

7. In claim 5, The above R 25 Inland R 28 may be the same or different, and are hydrogen, hydroxy or (C1-C3)alkyl, The above R 29 Inland R 32 may be the same or different, and are hydrogen, chlorine, amino, or (C1-C3)alkyl, The above R 33 Inland R 35 may be the same or different, and are hydrogen, (C1-C3)alkyl, or trifluoromethyl, and the R 36 and R 37 may be the same or different, and are hydrogen or (C1-C3)alkyl; R 36 and R 37 These are interconnected to form a six-ring ring, R 38 is hydrogen or (C1-C3)alkyl, m3 is 0 or 1, The above R 39 Inland R 42 A compound characterized in that each may be the same or different and is selected from hydrogen, fluorine, amino, (C1-C3)alkyl or (C1-C3)alkoxy.

8. In claim 1, A compound characterized in that in the above chemical formula 1, L has a structure represented by the following chemical formula 13: [Chemical Formula 13] wherein n is 1 to 30, The above L' is each independently -CH2-, -CO-, -CH(CH3)-, -(CH)2-, -COO-, -OCO-, -NR 101 -, -CHOH-, -CONH-, -NHCO-, -O-, -SO2-, -PO(OH)-, -PO(OCH3)-, , , unsubstituted or substituted cycloalkylene having 3 to 10 carbon atoms, unsubstituted or substituted 4 to 20-membered heterocycloalkylene containing at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted arylene having 3 to 10 carbon atoms, unsubstituted or substituted 4 to 20-membered heteroarylene containing at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted spirocycloalkylene having 5 to 10 carbon atoms, unsubstituted or substituted 5 to 13-membered heterospirocycloalkylene containing at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted 5 to 13-membered spiroheteroarylene containing at least one heteroatom selected from the group consisting of N, O and S, bicycloalkylene having 5 to 10 carbon atoms and N, Any one of 5 to 10 membered heterobicycloalkylenes containing at least one heteroatom selected from the group consisting of O and S, The above R 101 Silver hydrogen, (C1-C5)alkyl and is one of, and the n3 is one of 1 to 5, The above R 102 and R 103 may be the same or different, and are hydrogen or (C1-C5)alkyl, The above n1 is one of 1 to 10, The above substituted cycloalkylene, heterocycloalkylene, arylene, heteroarylene, spirocycloalkylene, spiroheterocycloalkylene, spiroheteroarylene, bicycloalkylene and heterobicycloalkylene are selected from the group consisting of hydroxy, carboxy, carbonyl, halogen, (C1-C5)alkyl, hydroxy(C1-C5)alkyl, (C1-C5)alkoxy, amino, -NH-Fmoc (fluorenylmethyloxycarbonyl), morpholino(C1-C5)alkyl, And at least one selected from the group consisting of (C1-C5)alkylsulfonyl is substituted, and n2 is one of 1 to 10.

9. In claim 8, wherein n is 1 to 15, The above L' is each independently -CH2-, -CO-, -CH(CH3)-, -(CH)2-, -COO-, -OCO-, -NR 101 -, -CHOH-, -CONH-, -NHCO-, -O-, -SO2-, -PO(OH)-, -PO(OCH3)-, , , , unsubstituted or substituted cycloalkylene having 3 to 6 carbon atoms, unsubstituted or substituted 4 to 20-membered heterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted arylene having 4 to 6 carbon atoms, unsubstituted or substituted 4 to 20-membered heteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted spirocycloalkylene having 5 to 10 carbon atoms, unsubstituted or substituted 5 to 13-membered spiroheterocycloalkylene comprising at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted 5 to 13-membered spiroheteroarylene comprising at least one heteroatom selected from the group consisting of N, O and S, bicycloalkylene having 5 to 10 carbon atoms and N, O and Any one of 5 to 10-membered heterobicycloalkylenes containing at least one heteroatom selected from the group consisting of S, The above R 101 is hydrogen, (C1-C3)alkyl, and is one of, and n3 is one of 1 to 5, wherein n1 is one of 1 to 5, and the substituted cycloalkylene, heterocycloalkylene, arylene, heteroarylene, spirocycloalkylene, spiroheterocycloalkylene, spiroheteroarylene, bicycloalkylene and heterobicycloalkylene are selected from the group consisting of hydroxy, carboxy, carbonyl, halogen, (C1-C5)alkyl, hydroxy(C1-C2)alkyl, (C1-C5)alkoxy, amino, -NH-Fmoc, A compound characterized in that at least one selected from the group consisting of , morpholino (C1-C2) alkyl, and (C1-C2) alkylsulfonyl is substituted, and n2 is one of 1 to 5.

10. In claim 1, The compound is characterized in that the compound is selected from the following group of compounds: (1) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (2) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethan-1-one; (3) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (4) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (5) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (6) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butan-1-one; (7) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (8) 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (9) 2-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one; (10) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (11) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (12) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (13) (4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (14) (4-(2-(2-aminobenzo[d]oxazol-6-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (15) (4-(2-(1H-indazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (16) (5-((4-(4-(2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (17) (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (18) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)(4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)phenyl)methanone; (19) (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (20) (5-((4-(2-(2-Aminobenzo[d]oxazol-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (21) (5-((5-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (22) (5-((4-((6-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyridin-3-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (23) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone; (24) (5-((4-(4-(2-(1H-indazol-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (25) (S)-(5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (26) ((S)-3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)((S)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)pyrrolidin-3-yl)methanone; (27) (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methanone; (28) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (29) (5-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (30) (S)-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrrolidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (31) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (32) 2-Amino-4-(5-(2-(4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperazin-1-yl)ethoxy)-2,4-dichlorophenyl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide; (33) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)methanone; (34) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (35) (4-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (36) (5-((4-((1r,4r)-4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (37) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)sulfonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (38) 2-((1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)piperidin-4-yl)amino)-4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide; (39) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (40) (5-((4-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-methoxybenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (41) (5-(((R)-4-(((1r,4R)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (42) 2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)propan-1-one; (43) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2-fluorobenzyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (44) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)propan-1-one; (45) (S)-(5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (46) (5-((9-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (47) (5-((4-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (48) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)propan-1-one; (49) (5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (50) (S)-(5-((4-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (51) (5-((4-(2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)-2-hydroxyethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (52) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (53) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (54) (R)-2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (55) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (56) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (57) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (58) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (59) 1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (60) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (61) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (62) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (63) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidine-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (64) (S)-(5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholine-4-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (65) 1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (66) (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (67) (S)-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (68) (5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (69) (5-((4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (70) 1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (71) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (72) (5-((1-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (73) (S)-(5-((4-((1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclopropyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (74) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (75) (S)-(5-((4-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (76) (5-((4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (77) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (78) (S)-2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (79) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-((R)-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)propan-1-one; (80) (5-((4-((2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (81) (5-((4-((1-((5-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)pyrazin-2-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (82) (S)-(5-((4-((2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholino)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (83) (S)-1-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)morpholino)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (84) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (85) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (86) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-2-(1-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazole-4-carbonyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (87) (5-((4-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (88) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (89) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (90) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)ethan-1-one; (91) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)ethan-1-one; (92) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)amino)piperidin-1-yl)ethan-1-one; (93) (5-(((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)(2-(2-methoxyethoxy)ethyl)amino)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (94) (5-(2-(1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperidin-4-yl)-5,8,11,14-tetraoxa-2-azapentadecyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (95) N-(15-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide; (96) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-N-(2-(2-methoxyethoxy)ethyl)acetamide; (97) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-N-(2,5,8,11-tetraoxatrican-13-yl)acetamide; (98) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide; (99) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)cyclohexyl)methanone; (100) (5-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)propoxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (101) (5-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)propoxy)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (102) (4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (103) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one; (104) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)ethan-1-one; (105) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (106) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)cyclohexyl)methanone; (107) (4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (108) 1-(4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (109) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (110) 1-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (111) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (112) (5-((4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (113) 2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)azetidin-1-yl)ethan-1-one; (114) (5-((4-(4-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (115) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (116) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (117) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (118) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (119) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(3-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxamide; (120) (2S,4S)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-4-(3-(4-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)acetyl)piperazin-1-yl)propoxy)pyrrolidine-1,2-dicarboxamide; (121) (2R,4S)-4-(2-(4-(2-(5-(2-amino-6-(ethylcarbamoyl)thieno[2,3-d]pyrimidin-4-yl)-2,4-dichlorophenoxy)ethyl)piperazin-1-yl)-2-oxoethoxy)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1,2-dicarboxamide; (122) (2R,4S)-N1-(5-(2-(tert-butyl)pyrimidin-4-yl)-4-methylthiazol-2-yl)-4-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (123) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (124) (S)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (125) (S)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-2-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (126) (S)-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (127) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (128) (4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (129) (4-(2'-amino-5-fluoro-6-morpholino-[4,5'-bipyrimidin]-2-yl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (130) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (131) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (132) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (133) (S)-(5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-fluorobenzoyl)-3-(hydroxymethyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (134) (5-((4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-3-fluorobenzoyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (135) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (136) (5-((4-((1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (137) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (138) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (139) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (140) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)morpholin-2-yl)((S)-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (141) (4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (142) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (143) (5-((4-(8-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-8-azaspiro[4.5]decan-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (144) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (145) (7-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (146) (S)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (147) 1-(4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (148) (4-((4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (149) (S)-2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (150) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (151) 2-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (152) (R)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (153) (R)-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (154) (R)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (155) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (156) (S)-2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (157) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (158) (4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (159) (4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (160) 1-(4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (161) 1-(4-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (162) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-(1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (163) 2-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (164) 2-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (165) (3-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)azetidin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (166) 2-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1H-pyrazol-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (167) 2-(4-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-1H-pyrazol-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (168) (5-((4-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)azetidin-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (169) (5-((2-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (170) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (171) 2-(1-(2'-amino-5-fluoro-6-morpholino-[2,5'-bipyrimidin]-4-yl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (172) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (173) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (174) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (175) 1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (176) (5-((4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (177) (1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methanone; (178) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (179) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (180) 6-(2-Aminopyrimidin-5-yl)-N-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide; (181) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (182) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methanone; (183) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl) methyl)-1,4-diazepan-1-yl)methanone; (184) (6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (185) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (186) (2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (187) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (188) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (189) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (190) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)ethan-1-one; (191) 2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)ethan-1-one; (192) (S)-2-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (193) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (194) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (195) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (196) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (197) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (198) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (199) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (200) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (201) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (202) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (203) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (204) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (205) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (206) (4-((5-(2-aminopyrimidin-5-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (207) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (208) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (209) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (210) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone; (211) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (212) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (213) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (214) (4-((6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (215) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)methanone; (216) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (217) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (218) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (219) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (220) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (221) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone; (222) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(4-hydroxy-7-isopropylbenzo[d]isoxazole-5-carbonyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (223) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone; (224) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (225) (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-(hydroxymethyl)piperazin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (226) 1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (227) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)-[1,4'-bipiperidin]-1'-yl)methanone; (228) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)azetidin-1-yl)methanone; (229) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (230) 1-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (231) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (232) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (233) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(5-chloro-2,4-dihydroxybenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (234) (5-((4-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (235) 1-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (236) (5-((4-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (237) (5-((4-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (238) 1-(3-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-4-hydroxypiperidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (239) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)azetidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)methanone; (240) (5-((4-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (241) (5-((4-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (242) 1-(7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (243) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methanone; (244) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)amino)piperidin-1-yl)methanone; (245) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (246) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methanone; (247) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)methanone; (248) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methanone; (249) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)methanone; (250) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (251) (5-((7-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (252) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)-3-fluorophenyl)methanone; (253) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)ethan-1-one; (254) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one; (255) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (256) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)ethan-1-one; (257) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (258) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((2-(4-hydroxy-5-isopropylbenzo[d]isoxazole-7-carbonyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (259) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (260) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)methanone; (261) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)morpholin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)methanone; (262) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (263) (5-((4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (264) 1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decan-8-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (265) N-(2-(2-(3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide; (266) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)ethan-1-one; (267) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (268) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4-diazepan-1-yl)ethan-1-one; (269) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)methyl)piperidin-1-yl)ethan-1-one; (270) (R)-2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-(hydroxymethyl)piperazin-1-yl)ethan-1-one; (271) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(methylsulfonyl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (272) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylpiperidine-4-carboxamide; (273) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)methanone; (274) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N-(2-(2-(2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperidine-4-carboxamide; (275) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-(1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methanone; (276) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(16-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methanone; (277) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-1-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)piperidin-1-yl)ethan-1-one; (278) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-hydroxypiperidin-4-yl)-N-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)(methyl)amino)ethyl)-N-methylacetamide; (279) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)phenyl)methanone; (280) (5-((4-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carbonyl)phenyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (281) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2,5,8,11-tetraoxatridecan-13-yl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (282) (S)-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2-(2-methoxyethoxy)ethyl)piperazin-2-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (283) Diethyl ((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phosphonate; (284) Diethyl ((4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(4-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)carbamoyl)phenyl)methyl)phosphonate; (285) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methanone; (286) (5-((4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (287) (5-((4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)-4-hydroxypiperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (288) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-4-hydroxypiperidin-4-yl)ethan-1-one; (289) (1'-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-[1,4'-bipiperidin]-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (290) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1'-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-[1,4'-bipiperidin]-4-yl)methanone; (291) (5-((4-((1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (292) (5-((4-(1-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)piperidin-4-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (293) (5-((9-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (294) (5-((2-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (295) (5-((4-(1-(4-(2-(2-aminopyrimidin-5-yl))-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclohexane-1-carbonyl)azetidin-3-yl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (296) (5-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1,4'-bipiperidin]-1'-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (297) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (298) N-(3-(2-chloro-5-fluorophenyl)-6-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (299) N-(3-(2-chloro-5-fluorophenyl)-6-(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (300) N-(4-(1-(2-chloro-5-fluorophenyl)-7-(3-fluoro-5-(trifluoromethyl)benzamido)-3-oxoisoindolin-5-yl)phenyl)-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carboxamide; (301) N-(3-(2-chloro-5-fluorophenyl)-6-(4-((2-(2-(2-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamoyl)phenyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (302) N-(3-(2-chloro-5-fluorophenyl)-6-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)-1-oxoisoindolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (303) (5-((4-((3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)azetidin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (304) (5-((4-(4-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)benzyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (305) Methyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinate; (306) Ethyl hydrogen ((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)phenyl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phosphonate; (307) 2-(4-amino-1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (308) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (309) (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinic acid; (310) Methyl (3-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-3-oxopropyl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-3-oxopropyl)phosphinate; (311) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (312) (1-((2-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (313) (1-((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (314) (1-((2-(2-amino-4-methylpyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (315) (1-((2-(2-amino-4-(trifluoromethyl)pyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (316) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(1-((1-(( 2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)azetidin-3-yl)methanone; (317) (1-((2-(6-amino-5-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (318) (1-((2-(6-amino-5-methoxypyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (319) (S)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)methanone; (320) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(morpholinomethyl)piperazin-1-yl)methanone; (321) 2-(4-amino-1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (322) (1-((2-(5-amino-6-methoxypyrazin-2-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (323) (1-((2-(5-amino-6-methoxypyrazin-2-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (324) (5-((4-(4-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (325) (5-((4-((1-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (326) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (327) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)ethan-1-one; (328) 2-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)-1-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidin-1-yl)ethan-1-one; (329) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (330) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(4 -((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)cyclohexyl)methanone; (331) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(7-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)cyclohexyl)methanone; (332) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)azetidine-1-carbonyl)cyclohexyl)methanone; (333) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-(9-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-carbonyl)cyclohexyl)methanone; (334) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)methanone; (335) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-(4-((4-( (2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)methanone; (336) (6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (337) (1-((6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (338) 2-(4-amino-1-(6-(2-aminopyrimidin-5-yl)-8-morpholinoimidazol-2-carbonyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (339) (2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)methanone; (340) 2-(4-amino-1-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperidin-4-yl)-1-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)ethan-1-one; (341) Methyl (5-(6-(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrimidin-2-yl)carbamate; (342) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1S,4r)-4-((S)-4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)cyclohexyl)methanone; (343) Methyl(5-(2-((4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)-8-morpholinoimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl)carbamate; (344) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)piperazin-1-yl)methanone; (345) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(5-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methoxy)pyrazin-2-yl)methanone; (346) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)methanone; (347) (1-((2-(6-amino-5-methylpyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (348) (R)-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)pyrrolidin-3-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (349) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)((1r,4r)-4-(((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pyrazin-2-yl)oxy)methyl)cyclohexyl)methanone; (350) (1-((2-(6-amino-2-methylpyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (351) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1s,4s)-4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazine-1-carbonyl)cyclohexyl)methanone; (352) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)((1r,4r)-4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)methanone; (353) (5-((4-(4-(((1r,4r)-4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (354) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((1-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)oxy)piperidin-1-yl)methanone; (355) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazin-1-yl)methanone; (356) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)(5-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)oxy)pyrazin-2-yl)methanone; (357) (4-amino-1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)methanone; (358) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)methanone; (359) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)phenyl)methanone; (360) (5-((4-((4'-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (361) (1-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-(2-(2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)ethyl)piperidin-4-yl)piperazin-1-yl)methanone; (362) (1-((2-(2-aminobenzo[d]oxazol-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (363) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(3-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)methanone; (364) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)piperidin-1-yl)methanone; (365) (5-((4-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)cyclobutane-1-carbonyl)piperazin-1-yl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (366) (1r,4r)-N-(6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-2-yl)-4-((4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexane-1-carboxamide; (367) (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carbonyl)piperidin-1-yl)pyrimidin-5-yl)urea; (368) 1-((R)-1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-(3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidin-1-yl)pyrimidin-5-yl)urea; (369) (R)-1-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)-3-(2-((4-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-4-oxobutyl)amino)pyrimidin-5-yl)urea; (370) N-(6-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)acetamide; (371) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)methanone; (372) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-methylpiperidin-4-yl)(1'-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-[4,4'-bipiperidin]-1-yl)methanone; (373) (R)-N-(2-chloro-5-(4-((1-(3-((5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-5-oxopentyl)oxy)phenyl)ethyl)amino)quinazolin-6-yl)pyridin-3-yl)methanesulfonamide; (374) (1r,4r)-4-((1-oxo-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-1,2-dihydroisoquinolin-8-yl)amino)cyclohexyl 4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperidin-1-yl)methyl)piperidine-1-carboxylate; (375) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((6-(2,4-dihydroxy-5-isopropylbenzoyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)methyl)piperidin-1-yl)methanone; (376) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-((6-(2,4-dihydroxy-5-isopropylbenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl)piperidin-1-yl)methanone; (377) (2-(2-aminopyrimidin-5-yl)-4-morpholino-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)piperidin-1-yl)methyl)phenyl)methanone; (378) (5-((4-((1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (379) (5-((4-((4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (380) (5-((4-((1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (381) (5-(4-((4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (382) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (383) (2S,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (384) (2R,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (385) (2R,3R)-N1-(8-(tert-butyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl)-3-(2-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)pyrrolidine-1,2-dicarboxamide; (386) (R)-2-amino-6-(2-(1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)ethyl)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one; (387) (R)-2-amino-6-(2-(1-((1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one; (388) (S)-6-(4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide; (389) (S)-6-(4-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide; (390) (S)-6-(4-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)-4-oxobutanamido)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)hexanamide; (391) (1r,4r)-4-((1-oxo-3-propyl-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-1,2-dihydroisoquinolin-8-yl)amino)cyclohexyl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (392) 1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-5-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)pentane-1,5-dione; (393) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-4-fluoropiperidin-4-yl)(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methanone; (394) (1-((2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (395) (6-(2-aminobenzo[d]oxazol-5-yl)imidazo[1,2-a]pyridin-3-yl)(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)piperazin-1-yl)methanone; (396) (4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)((1r,4r)-4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)cyclohexyl)methanone; (397) (E)-1-(4-(4-(2-Aminobenzo[d]oxazol-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)but-2-ene-1,4-dione; (398) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (399) (5-((4-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (400) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(8-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone; (401) (5-((3-(8-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (402) (1r,4r)-4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)cyclohexyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (403) 1-(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidine-4-carbonyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (404) 1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (405) (1r,4r)-4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazine-1-carbonyl)cyclohexyl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (406) 1-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carbonyl)piperidin-4-yl 4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-1-carboxylate; (407) (1r,4R)-4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)cyclohexyl(3-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propyl)carbamate; (408) (E)-1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)but-2-ene-1,4-dione; (409) 1-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-4-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)butane-1,4-dione; (410) (5-((4-(((1r,4r)-4-(4-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-carbonyl)cyclohexyl)methyl)piperazin-1-yl)methyl)isoindolin-2-yl)(2,4-dihydroxy-5-isopropylphenyl)methanone; (411) 2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (412) 4-(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidine-4-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (413) 6-(2-Aminobenzo[d]oxazol-5-yl)-N-(3-(4-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidine-4-carbonyl)piperazin-1-yl)propyl)imidazo[1,2-a]pyridine-3-carboxamide; (414) (4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-3,3-difluoropiperidin-1-yl)(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methanone; (415) (4-(2-((2-amino-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-6-yl)amino)ethyl)piperazin-1-yl)(1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)methanone; (416) (4-(2-((2-amino-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-6-yl)amino)ethyl)piperazin-1-yl)(1-(4-(2-aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)methanone; (417) (4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)((1r,3r)-3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)cyclobutyl)methanone; (418) (1-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)(3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)oxy)azetidin-1-yl)methanone; (419) (1r,4r)-4-((2-carbamoyl-5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)phenyl)amino)cyclohexyl 4-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)piperidine-1-carboxylate; (420) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(4-((4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-1-yl)methyl)phenyl)piperazin-2-one; (421) 4-((2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-(2-(1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)ethyl)piperazin-2-one; (422) 4-(2-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperazin-2-one; (423) 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)pyridin-2(1H)-one; (424) 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)piperidin-2-one; and (425) 4-(2-(2-aminopyrimidin-5-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-1-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)pyridin-2(1H)-one.

11. A pharmaceutical composition for treating or preventing cancer, comprising a compound according to any one of claims 1 to 10 as an active ingredient.

12. In claim 11, The above cancer disease is, A pharmaceutical composition characterized in that it is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophagus cancer, thyroid cancer, kidney cancer, and rectal cancer.

13. In claim 11, The above cancer disease is, A pharmaceutical composition characterized in that the cancer is related to heat shock protein 90 (HSP90) or phosphoinositide 3-kinase (PI3K).

14. In claim 13, The above pharmaceutical composition, A pharmaceutical composition characterized by inhibiting the activity of HSP90 or PI3K.

15. A health functional food composition for improving or preventing cancer, comprising a compound according to any one of claims 1 to 10 as an active ingredient.

16. In claim 15, The above cancer disease is, A health functional food composition characterized by being selected from the group consisting of breast cancer, lung cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or cervical cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, and rectal cancer.

17. A method for treating a disease related to HSP90 or PI3K, comprising administering a compound according to any one of claims 1 to 10.

18. A method for degrading an HSP90 or PI3K target protein, comprising administering a compound according to any one of claims 1 to 10.

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